Is ALK p.Val581Phe (c.1741G>T) pathogenic?

ALK p.Val581Phe (c.1741G>T) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-10). AlphaMissense: likely benign (0.1073); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Val581Phe (c.1741G>T)?

ALK p.Val581Phe (c.1741G>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Val581Phe (c.1741G>T) in the general population?

ALK p.Val581Phe (c.1741G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Val581Phe (c.1741G>T)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

ALK p.Val581Phe

c.1741G>T · rs1666203352 · VCV836289

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.78	GERP -4.4
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	5.992	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Val581Phe
Coding: c.1741G>T
MANE Select: NM_004304
dbSNP: rs1666203352
Type: single nucleotide variant
Location: chr2:29296964 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 581: 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.Val581= Likely benign ★★ same residue
ALK p.Val581Ala Uncertain significance ★ ⚠ same residue
ALK p.Val581Ile Uncertain significance ★ ⚠ same residue
ALK p.Val581Gly 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

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-val581phe (accessed [today's date]).

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