The NRAS c.71T>A (p.Ile24Asn) variant has been reported in ClinVar and is classified as Likely Pathogenic by the ClinGen RASopathy expert panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity under the NRAS RASopathy framework.2 In expert-panel-reviewed functional evidence, RAS activation assays showed mildly increased GTP-bound RAS with enhanced MAPK phosphorylation, and a zebrafish model showed developmental and craniofacial defects that were rescued by MEK inhibition, supporting an abnormal gain-of-function effect.3 Computational evidence supports a damaging missense effect, with REVEL 0.863 above the PP3 threshold of 0.7, SpliceAI showing no significant splice impact with a maximum delta score of 0.00, and BayesDel 0.159947.4
Final classification
Likely Pathogenic
PS3PS4PM2PM6PP3PP5
NRAS
c.71T>A
p.Ile24Asn
This variant
The NRAS c.71T>A (p.Ile24Asn) variant has been reported in ClinVar and is classified as Likely Pathogenic by the ClinGen RASopathy expert panel.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule11 (1 Pathogenic.Strong + 1 Pathogenic.Moderate) with applied criteria: PS3 supporting, PS4 moderate, PM2 supporting, PM6 strong, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.
Classification rationale
PS3PS4PM2PM6PP3PP5
Likely Pathogenic
NRAS c.71T>A
PS3 + PS4 + PM2 + PM6 + PP3 + PP5
→
Likely Pathogenic
3
clinvar ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
revelspliceai ↗bayesdelcspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_002524.4 · variants mapped to exon structure
NRAS
NM_002524.4
Fetching transcript structure from UCSC…
Applied criteria · 6 applied · 12 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 6
Strength
Supporting
Moderate
Strong
Very strong
PS3
supporting
review
Pathogenic
In expert-panel-reviewed functional evidence, RAS activation assays in 293T cells showed mildly increased GTP-bound RAS with enhanced MAPK phosphorylation, and a zebrafish model showed developmental and craniofacial defects that were rescued by MEK inhibition. This supports an abnormal gain-of-function effect consistent with the NRAS RASopathy mechanism.
ClinVar expert-panel summary reports abnormal RAS activation and MAPK signaling plus a supportive zebrafish model.The VCEP functional-study file lists approved NRAS assay types including RAS activation and downstream signaling assays.
PS4
moderate
review
Pathogenic
This variant has been reported in 4 probands with features of RASopathy in expert-panel-reviewed evidence, which the NRAS RASopathy expert panel used to apply PS4 at Moderate strength.
ClinVar expert-panel summary states 4 probands with RASopathy and PS4_Moderate.
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the NRAS RASopathy requirement for PM2 at Supporting strength.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
PM6
strong
review
Pathogenic
Expert-panel-reviewed evidence reports this variant as de novo in 2 individuals with features of RASopathy, but with unconfirmed parental relationships. Under the NRAS RASopathy point-based framework, this was used to apply PM6 at Strong strength.
ClinVar expert-panel summary states 2 de novo occurrences with unconfirmed parental relationships and PM6_Strong.
PP3
supporting
Pathogenic
For this missense variant, the REVEL score is 0.863, which is above the NRAS RASopathy PP3 threshold of 0.7. SpliceAI predicts no splice effect with a maximum delta score of 0.00, supporting interpretation as a missense effect rather than a splicing mechanism. BayesDel is 0.159947 and does not contradict a damaging missense interpretation.
REVEL 0.863.SpliceAI max delta 0.00.BayesDel 0.159947.
Assessed · not applied
· 5 not met · 7 not assessed
Pathogenic
PS1
No reviewed evidence was identified showing the same amino acid change established as pathogenic from a different nucleotide change in the permitted NRAS RASopathy framework.
PS2
Available evidence describes de novo occurrences with unconfirmed parental relationships, so confirmed maternity and paternity were not established for PS2.
PM1
Residue 24 is outside the NRAS RASopathy PM1 domains defined for this specification: P-loop amino acids 10-17 and Switch I amino acids 25-40, as well as SW2 amino acids 57-64 and SAK amino acids 145-156.
PM5
No reviewed evidence was identified confirming a different pathogenic or likely pathogenic amino acid substitution at this same codon within the permitted RASopathy framework, so PM5 was not applied from the currently reviewed sources.
PP1
No segregation data were identified to show that this variant co-segregates with RASopathy across informative meioses.
Benign
BA1
This variant is absent from gnomAD, which is below the BA1 threshold of at least 0.05% filtering allele frequency.
BS1
This variant is absent from gnomAD, which is below the BS1 threshold of at least 0.025% filtering allele frequency.
BS2
No evidence was identified showing this variant in unaffected individuals at a level sufficient for BS2 under the NRAS RASopathy point-based framework.
BS4
No non-segregation data were identified to show that this variant fails to track with disease in informative relatives.
BP2
No evidence was identified showing this variant in cis or trans with an alternative pathogenic molecular explanation sufficient for BP2 point assignment.
BP4
BP4 is not met because the REVEL score is 0.863, which is above the benign-supporting threshold of 0.3 or lower for missense variants.
BP5
No evidence was identified showing an alternative molecular explanation in a different gene or a phenotype fully explained by another cause sufficient for BP5 point assignment.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.863. BayesDel score = 0.159947.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID 21263000
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
supporting
→PS4
moderate
→PM6
strong
PMID 22855653
Found
Structured finding pending for this record — see source link.
Applied to
→PS4
moderate
→PM6
strong
PMID 28594414
Found
Structured finding pending for this record — see source link.
Applied to
→PS4
moderate
Sources & reference links