Is ALK p.Gly199Arg (c.595G>C) pathogenic?

ALK p.Gly199Arg (c.595G>C) is classified Uncertain significance in ALK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: ambiguous (0.5011); Absent from gnomAD v4.1; Associated with neuroblastoma, susceptibility to, 3.

What condition is associated with ALK p.Gly199Arg (c.595G>C)?

ALK p.Gly199Arg (c.595G>C) is associated with neuroblastoma, susceptibility to, 3 (ClinVar).

How common is ALK p.Gly199Arg (c.595G>C) in the general population?

ALK p.Gly199Arg (c.595G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ALK p.Gly199Arg (c.595G>C)?

AlphaMissense predicts ambiguous (score 0.5011) — an in-silico prediction, not a clinical call.

ALK p.Gly199Arg

c.595G>C · VCV4809616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5011 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

neuroblastoma, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.5011	ambiguous
REVEL	0.5	indeterminate
SaProt	LLR -7.34	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	27.6	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.Gly199Arg
Coding: c.595G>C
MANE Select: NM_004304
Type: single nucleotide variant
Location: chr2:29920065 (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

neuroblastoma, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALK p.Gly199Ala Uncertain significance ★★ ⚠ same residue
ALK p.Gly199Asp Uncertain significance ★★ ⚠ same residue
ALK p.Gly199Val Uncertain significance ★★ ⚠ same residue
ALK p.Gly199= Benign/Likely benign ★★ 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-gly199arg (accessed [today's date]).

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