Is ALK p.Ile840Phe (c.2518A>T) pathogenic?

ALK p.Ile840Phe (c.2518A>T) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: likely pathogenic (0.8665); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Ile840Phe (c.2518A>T)?

ALK p.Ile840Phe (c.2518A>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Ile840Phe (c.2518A>T) in the general population?

ALK p.Ile840Phe (c.2518A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Ile840Phe (c.2518A>T)?

AlphaMissense predicts likely pathogenic (score 0.8665) — an in-silico prediction, not a clinical call.

ALK p.Ile840Phe

c.2518A>T · VCV4679545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8665 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8665	likely pathogenic
REVEL	0.199	benign-leaning
SaProt	LLR -15.00	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.92	GERP 0.76, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 26 kb · p 0.039 · regional, not allelic
Overall
CADD	23.6	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

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.Ile840Phe
Coding: c.2518A>T
MANE Select: NM_004304
Type: single nucleotide variant
Location: chr2:29232418 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 840: a β-strand

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.Ile840Thr Uncertain significance ★★ ⚠ same residue
ALK p.Ile840Val Uncertain significance ★★ ⚠ same residue
ALK p.Ile840= Likely benign ★★ same residue
ALK p.Ile840Ser Uncertain significance ★ ⚠ same residue
ALK p.Ile840Met 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

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-ile840phe (accessed [today's date]).

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