Is ALK p.Ala371Thr (c.1111G>A) pathogenic?

ALK p.Ala371Thr (c.1111G>A) is classified Benign/Likely benign in ALK (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0669); Rare (popmax 0.294%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Ala371Thr (c.1111G>A)?

ALK p.Ala371Thr (c.1111G>A) is associated with hereditary neoplastic syndrome, ovarian cancer, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Ala371Thr (c.1111G>A) in the general population?

ALK p.Ala371Thr (c.1111G>A) is rare (popmax 0.294%, eas) (gnomAD).

What do computational predictors say about ALK p.Ala371Thr (c.1111G>A)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

ALK p.Ala371Thr

c.1111G>A · rs149968229 · VCV133483

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.294%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.06, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	17.72	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.294% East Asian · 132/44,882 alleles

Filtering AF 0.253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.238%

Overall 0.00966% 156/1,614,168 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.294%	340
Remaining individualsnot grpmax-eligible	0.0368%	2,718
South Asian	0.0011%	91,078

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.Ala371Thr
Coding: c.1111G>A
MANE Select: NM_004304
dbSNP: rs149968229
Type: single nucleotide variant
Location: chr2:29531958 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 371: the mam 1 domain

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

Also linked: ovarian cancer neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Ala371Asp Uncertain significance ★★ ⚠ same residue
ALK p.Ala371Gly Uncertain significance ★★ ⚠ same residue
ALK p.Ala371= Likely benign ★ same residue
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

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-ala371thr (accessed [today's date]).

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