Is ALK p.Phe1174Cys (c.3521T>G) pathogenic?

ALK p.Phe1174Cys (c.3521T>G) is classified Likely pathogenic in ALK (ClinVar, Single submitter, 2 submitters; last evaluated 2023-05-11). AlphaMissense: likely pathogenic (0.9959); Absent from gnomAD v4.1; Associated with ALK-related disorder.

What condition is associated with ALK p.Phe1174Cys (c.3521T>G)?

ALK p.Phe1174Cys (c.3521T>G) is associated with ALK-related disorder (ClinVar).

How common is ALK p.Phe1174Cys (c.3521T>G) in the general population?

ALK p.Phe1174Cys (c.3521T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Phe1174Cys (c.3521T>G)?

AlphaMissense predicts likely pathogenic (score 0.9959) — an in-silico prediction, not a clinical call.

ALK p.Phe1174Cys

c.3521T>G · rs1057519697 · VCV375887

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9959 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ALK-related disorder

Computational evidence

Protein change
AlphaMissense	0.9959	likely pathogenic ✓ concordant with ClinVar · top 6% in ALK
REVEL	0.953	strongly pathogenic-leaning
SaProt	LLR -16.01	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	32.0	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.Phe1174Cys
Coding: c.3521T>G
MANE Select: NM_004304
dbSNP: rs1057519697
Type: single nucleotide variant
Location: chr2:29220830 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 1174: a UniProt-annotated variant site (in nblst3); a UniProt-annotated variant site (in nblst3; somatic mutation); a UniProt-annotated variant site (in nblst3; somatic mutation; constitutively activated; retained in the endoplasmic reticulum and golgi compartments); the protein kinase domain

Full ALK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ALK-related disorder

Similar variants

ALK p.Phe1174= Likely benign ★ same residue
ALK p.Phe1174Ile Pathogenic same residue
ALK p.Phe1174Leu Pathogenic same residue
ALK p.Phe1174Val Pathogenic same residue
ALK p.Arg1575Cys Uncertain significance ★★ ⚠ same condition
ALK p.Glu1161Lys Uncertain significance ★★ ⚠ same condition
ALK p.Pro835Leu Uncertain significance ★★ ⚠ same condition
ALK p.Ser21Phe 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-phe1174cys (accessed [today's date]).

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