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
NRAS
Final classification
Likely Pathogenic
NRAS c.71T>A · p.Ile24Asn
NRAS
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 ↗
Gene diagram
· NM_002524.4 · variants mapped to exon structure
NRAS
NM_002524.4
Fetching transcript structure from UCSC…
Applied criteria · 6 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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
→PM6 supports · met
→PS3 supports · met
→PS4 supports · met
PMID 22855653
Found
Structured finding pending for this record — see source link.
Applied to
→PM6 supports · met
→PS4 supports · met
PMID 28594414
Found
Structured finding pending for this record — see source link.
Applied to
→PS4 supports · met
Sources & reference links