Is ALK p.Val1111Ala (c.3332T>C) pathogenic?

ALK p.Val1111Ala (c.3332T>C) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-10). AlphaMissense: likely pathogenic (0.9655); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Val1111Ala (c.3332T>C)?

ALK p.Val1111Ala (c.3332T>C) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Val1111Ala (c.3332T>C) in the general population?

ALK p.Val1111Ala (c.3332T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ALK p.Val1111Ala (c.3332T>C)?

AlphaMissense predicts likely pathogenic (score 0.9655) — an in-silico prediction, not a clinical call.

ALK p.Val1111Ala

c.3332T>C · rs558282902 · VCV1434723

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9655	likely pathogenic
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -9.67	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 26 kb · p 0.039 · regional, not allelic
Overall
CADD	29.1	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 0.00223% East Asian · 1/44,860 alleles

Overall 6.2e-05% 1/1,613,912 alleles · very rare exomes 0/1,461,862 · genomes 1/152,050 · joint denominator

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.Val1111Ala
Coding: c.3332T>C
MANE Select: NM_004304
dbSNP: rs558282902
Type: single nucleotide variant
Location: chr2:29223369 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB

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.Val1111Met Uncertain significance ★★ ⚠ same residue
ALK p.Val1111Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Val1111= 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-val1111ala (accessed [today's date]).

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