Is ALK p.Ala741Asp (c.2222C>A) pathogenic?

ALK p.Ala741Asp (c.2222C>A) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-20). AlphaMissense: likely pathogenic (0.9941); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Ala741Asp (c.2222C>A)?

ALK p.Ala741Asp (c.2222C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Ala741Asp (c.2222C>A) in the general population?

ALK p.Ala741Asp (c.2222C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Ala741Asp (c.2222C>A)?

AlphaMissense predicts likely pathogenic (score 0.9941) — an in-silico prediction, not a clinical call.

ALK p.Ala741Asp

c.2222C>A · rs1664477105 · VCV1787948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9941 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9941	likely pathogenic · top 7% in ALK
REVEL	0.535	indeterminate
SaProt	LLR -10.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 11 kb · p 0.0014 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ALK
Protein: p.Ala741Asp
Coding: c.2222C>A
MANE Select: NM_004304
dbSNP: rs1664477105
Type: single nucleotide variant
Location: chr2:29239813 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 741: an α-helix

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.Ala741= Likely benign ★★ same residue
ALK p.Ala741Thr Uncertain significance ★ ⚠ same residue
ALK p.Ala741Gly Uncertain significance ★ ⚠ 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-ala741asp (accessed [today's date]).

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