Is ALK p.Gly199Val (c.596G>T) pathogenic?

ALK p.Gly199Val (c.596G>T) is classified Uncertain significance in ALK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-09). AlphaMissense: ambiguous (0.4296); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with ALK p.Gly199Val (c.596G>T)?

ALK p.Gly199Val (c.596G>T) is associated with hereditary neoplastic syndrome, neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Gly199Val (c.596G>T) in the general population?

ALK p.Gly199Val (c.596G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ALK p.Gly199Val (c.596G>T)?

AlphaMissense predicts ambiguous (score 0.4296) — an in-silico prediction, not a clinical call.

ALK p.Gly199Val

c.596G>T · rs1292996434 · VCV1750781

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4296	ambiguous
REVEL	0.462	indeterminate
SaProt	LLR -7.54	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 670 kb · p 0.12 · regional, not allelic
Overall
CADD	26.4	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 0.00167% Admixed American · 1/60,014 alleles

Overall 0.000186% 3/1,614,092 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.47e-05%	1,180,059

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.Gly199Val
Coding: c.596G>T
MANE Select: NM_004304
dbSNP: rs1292996434
Type: single nucleotide variant
Location: chr2:29920064 (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.Gly199Ala Uncertain significance ★★ ⚠ same residue
ALK p.Gly199Asp Uncertain significance ★★ ⚠ same residue
ALK p.Gly199= Benign/Likely benign ★★ same residue
ALK p.Gly199Arg Uncertain significance ★ ⚠ same residue
ALK p.Gly199Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
ALK p.Gly199Ser Uncertain significance ★ ⚠ same residue
ALK p.Arg1275Gln Pathogenic ★★ same condition
ALK c.1154+5G>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-gly199val (accessed [today's date]).

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