NM_004304.4:c.3373G>A (p.Gly1125Ser) is a missense variant in exon 21 of ALK, residing within the tyrosine kinase domain P-loop (GAFGE motif). It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at the supporting level.1 In silico predictors support a deleterious effect: REVEL score 0.968 (strongly damaging) and BayesDel score 0.576 (damaging), meeting PP3 at the supporting level. SpliceAI predicts no splice impact (max delta 0.00).2 No variant-specific functional data, de novo reports, segregation data, or case-control studies are available. The variant is absent from ClinVar, COSMIC, and cancerhotspots.org. OncoKB classifies it as 'Unknown Oncogenic Effect'.3 With two supporting criteria (PM2_supporting + PP3_supporting) and no criteria met at moderate, strong, or benign levels, this variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 generic classification rules (PMID:25741868).4
ALK
Final classification
VUS
ALK c.3373G>A · p.Gly1125Ser
ALK
NM_004304.4:c.3373G>A (p.Gly1125Ser) is a missense variant in exon 21 of ALK, residing within the tyrosine kinase domain P-loop (GAFGE motif). It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at the supporting level.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
ALK c.3373G>A
PM2 + PP3
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_004304.4 · variants mapped to exon structure
ALK
NM_004304.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_004304.4:c.3373G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the non-VCEP threshold for PM2 (allele frequency <0.1% or absent).
Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.
✓
PP3
supporting
Pathogenic
In silico predictors support a deleterious effect: REVEL score 0.968 (above the 0.932 threshold commonly used for PP3) and BayesDel score 0.576 (above the 0.5 damaging threshold). SpliceAI predicts no splice impact (max delta 0.00).
REVEL 0.968 (damaging).BayesDel 0.576 (damaging).SpliceAI max delta 0.00 (no splice impact).
Assessed · not applied
Pathogenic
PS1
No alternate nucleotide change at c.3373 resulting in the same amino acid change has been identified as pathogenic in ClinVar or the literature.
PS2
No de novo occurrence data are available for this variant; no family studies have been identified.
PS3
No variant-specific functional data have been identified.
PS4
No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls are available.
PM1
Although Gly1125 resides within the ALK tyrosine kinase domain P-loop (GAFGE motif, aa 1125-1129), cancerhotspots.org does not identify this residue as a statistically significant hotspot, and no literature establishes that missense variants in the ALK kinase domain are a common mechanism of germline disease.
PM6
No de novo occurrence data are available; no family studies or trio sequencing reports were identified.
PP1
No co-segregation data are available for this variant.
PP2
No missense constraint data (Z-score, missense depletion metrics) are available for ALK to assess whether the gene has a low rate of benign missense variation.
PP4
No patient phenotype information is available to assess specificity for an ALK-related disorder.
PP5
No reputable source (ClinVar, diagnostic laboratory) has reported this variant as pathogenic.
Benign
BA1
NM_004304.4:c.3373G>A is absent from all gnomAD datasets; allele frequency does not exceed the BA1 threshold of >1%.
BS1
NM_004304.4:c.3373G>A is absent from all gnomAD datasets; allele frequency does not exceed the non-VCEP BS1 threshold of >0.3%.
BS2
No data are available demonstrating this variant has been observed in a healthy adult individual for a fully penetrant disorder.
BS3
No well-established in vitro or in vivo functional studies demonstrate that this variant has no deleterious effect on protein function or splicing.
BS4
No family segregation data are available to demonstrate lack of co-segregation with disease.
BP1
ALK has well-established pathogenic missense variants (e.g., p.Arg1275Gln in neuroblastoma predisposition), so a missense variant does not qualify for BP1, which requires that primarily truncating variants cause disease.
BP2
No data are available to demonstrate this variant has been observed in trans with a known pathogenic variant in ALK.
BP4
In silico predictors do not support a benign effect; REVEL score of 0.968 is strongly damaging, and BayesDel score of 0.576 is above the damaging threshold.
BP5
No evidence that this variant was found in a case with an alternate molecular basis for disease.
BP6
No reputable source has classified this variant as benign; the variant is absent from ClinVar.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
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.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.968. BayesDel score = 0.575979.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma
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.
Sources & reference links