Is GLA p.Val199Ala (c.596T>C) pathogenic?

GLA p.Val199Ala (c.596T>C) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.2629); Very rare (popmax 0.00175%, afr); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Val199Ala (c.596T>C)?

GLA p.Val199Ala (c.596T>C) is associated with Cardiovascular phenotype, Fabry disease (ClinVar).

How common is GLA p.Val199Ala (c.596T>C) in the general population?

GLA p.Val199Ala (c.596T>C) is very rare (popmax 0.00175%, afr) (gnomAD).

What do computational predictors say about GLA p.Val199Ala (c.596T>C)?

AlphaMissense predicts likely benign (score 0.2629) — an in-silico prediction, not a clinical call.

GLA p.Val199Ala

c.596T>C · rs781871113 · VCV246587

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.2629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2629	likely benign
REVEL	0.819	moderately pathogenic-leaning
SaProt	LLR -9.56	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · 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

Grpmax group 0.00175% African / African-American · 1/57,018 alleles

Filtering AF 9.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000335% 4/1,192,456 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00175%	57,018
European (non-Finnish)	0.000341%	293,034

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: GLA
Protein: p.Val199Ala
Coding: c.596T>C
dbSNP: rs781871113
Type: single nucleotide variant
Location: chrX:101400709 (GRCh38)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fabry disease

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/gla-p-val199ala (accessed [today's date]).

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