Is ALK p.Asp732Tyr (c.2194G>T) pathogenic?

ALK p.Asp732Tyr (c.2194G>T) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-18). AlphaMissense: ambiguous (0.4285); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Asp732Tyr (c.2194G>T)?

ALK p.Asp732Tyr (c.2194G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is ALK p.Asp732Tyr (c.2194G>T) in the general population?

ALK p.Asp732Tyr (c.2194G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Asp732Tyr (c.2194G>T)?

AlphaMissense predicts ambiguous (score 0.4285) — an in-silico prediction, not a clinical call.

ALK p.Asp732Tyr

c.2194G>T · VCV3285221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4285 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4285	ambiguous
REVEL	0.591	indeterminate
SaProt	LLR -8.42	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.39, phastCons 0.99
Regional constraint	o/e 0.45	unconstrained · MANE · 11 kb · p 0.0014 · regional, not allelic
Overall
CADD	24.2	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.Asp732Tyr
Coding: c.2194G>T
MANE Select: NM_004304
Type: single nucleotide variant
Location: chr2:29251115 (GRCh38)
Gene constraint: LOEUF 0.562 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.26 · 79 PDB
Residue 732: 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.Asp732= Likely benign ★★ same residue
ALK p.Asp732Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Asp732Glu Uncertain significance ★ ⚠ same residue
ALK p.Asp732fs 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-asp732tyr (accessed [today's date]).

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