Is ALK p.Gly925= (c.2775A>C) pathogenic?

ALK p.Gly925= (c.2775A>C) is classified Likely benign in ALK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-01). Rare (popmax 0.684%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Gly925= (c.2775A>C)?

ALK p.Gly925= (c.2775A>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Gly925= (c.2775A>C) in the general population?

ALK p.Gly925= (c.2775A>C) is rare (popmax 0.684%, nfe) (gnomAD).

ALK p.Gly925=

c.2775A>C · rs777406442 · VCV1795841

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.684%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.44	GERP -4.2, phastCons 0.12
Overall
CADD	3.623	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.684% European (non-Finnish) · 2,437/356,268 alleles

Filtering AF 0.661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.652%

Overall 0.572% 2,716/474,590 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.684%	146
Remaining individualsnot grpmax-eligible	0.439%	228
Middle Eastern	0.328%	305
African / African-American	0.217%	460
South Asian	0.18%	555
Ashkenazi Jewishnot grpmax-eligible	0.112%	890
East Asian	0.0811%	1,234
Finnishnot grpmax-eligible	0.0435%	2,298
Admixed American	0.0268%	3,737

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ALK
Protein: p.Gly925=
Coding: c.2775A>C
MANE Select: NM_004304
dbSNP: rs777406442
Type: single nucleotide variant
Location: chr2:29228924 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 925: an α-helix; a disulfide bond

Full ALK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALK p.Arg1275Gln Pathogenic ★★ same condition
ALK c.1154+5G>A Uncertain significance ★★ same condition
ALK c.1155-3C>T Uncertain significance ★★ same condition
ALK c.1282+3A>G Uncertain significance ★★ same condition
ALK c.1414+1G>A Uncertain significance ★★ same condition
ALK c.1414+3G>A Uncertain significance ★★ same condition
ALK c.1415-3T>C Uncertain significance ★★ same condition
ALK c.1546+4C>T Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/alk-p-gly925 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown