Is GLA p.Val339Ala (c.1016T>C) pathogenic?

GLA p.Val339Ala (c.1016T>C) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.2932); Very rare (popmax 0.000335%, nfe); Associated with GLA-related disorder.

What condition is associated with GLA p.Val339Ala (c.1016T>C)?

GLA p.Val339Ala (c.1016T>C) is associated with GLA-related disorder, Fabry disease, steroid-resistant nephrotic syndrome (ClinVar).

How common is GLA p.Val339Ala (c.1016T>C) in the general population?

GLA p.Val339Ala (c.1016T>C) is very rare (popmax 0.000335%, nfe) (gnomAD).

What do computational predictors say about GLA p.Val339Ala (c.1016T>C)?

AlphaMissense predicts likely benign (score 0.2932) — an in-silico prediction, not a clinical call.

GLA p.Val339Ala

c.1016T>C · rs869312211 · VCV222122

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000335%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GLA-related disorder

Computational evidence

Protein change
AlphaMissense	0.2932	likely benign
REVEL	0.698	pathogenic-leaning
SaProt	LLR -10.19	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 3.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	24.3	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 0.000335% European (non-Finnish) · 3/894,834 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000248% 3/1,209,923 alleles · very rare exomes 2/1,097,514 · genomes 1/112,409 · joint denominator

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.Val339Ala
Coding: c.1016T>C
MANE Select: NM_000169
dbSNP: rs869312211
Type: single nucleotide variant
Location: chrX:101398083 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 339: a β-strand

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

Disease context

GLA-related disorder

Also linked: Fabry disease steroid-resistant nephrotic syndrome

Similar variants

GLA p.Val339Glu Uncertain significance ★★ ⚠ same residue
GLA p.Val339= Likely benign ★★ same residue
GLA p.Val339Gly Likely pathogenic ★ same residue
GLA p.Val339Leu Uncertain significance ★ ⚠ same residue
GLA p.Val339fs Pathogenic ★ same residue
GLA c.1000-10G>A Likely pathogenic ★★ same condition
GLA c.1000-1G>A Pathogenic ★★ same condition
GLA c.1000-1G>C Pathogenic ★★ 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/gla-p-val339ala (accessed [today's date]).

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