Is ALK p.Ala624Val (c.1871C>T) pathogenic?

ALK p.Ala624Val (c.1871C>T) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-17). AlphaMissense: ambiguous (0.411); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Ala624Val (c.1871C>T)?

ALK p.Ala624Val (c.1871C>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Ala624Val (c.1871C>T) in the general population?

ALK p.Ala624Val (c.1871C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ALK p.Ala624Val (c.1871C>T)?

AlphaMissense predicts ambiguous (score 0.411) — an in-silico prediction, not a clinical call.

ALK p.Ala624Val

c.1871C>T · rs906659904 · VCV581121

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.411 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.411	ambiguous
REVEL	0.177	moderately benign-leaning
SaProt	LLR -11.34	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	26.1	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 0.00167% Admixed American · 1/60,018 alleles

Overall 0.000137% 2/1,461,884 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,018
African / African-American	0.00133%	75,028

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.Ala624Val
Coding: c.1871C>T
MANE Select: NM_004304
dbSNP: rs906659904
Type: single nucleotide variant
Location: chr2:29275443 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 624: the mam 2 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: neuroblastoma, susceptibility to, 3

Similar variants

ALK p.Ala624Gly Uncertain significance ★ ⚠ same residue
ALK p.Ala624Pro Uncertain significance ★ ⚠ same residue
ALK p.Ala624= 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-ala624val (accessed [today's date]).

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