Is GLA p.Val316Ile (c.946G>A) pathogenic?

GLA p.Val316Ile (c.946G>A) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.0762); Very rare (popmax 0.00527%, sas); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Val316Ile (c.946G>A)?

GLA p.Val316Ile (c.946G>A) is associated with Cardiovascular phenotype, Fabry disease (ClinVar).

How common is GLA p.Val316Ile (c.946G>A) in the general population?

GLA p.Val316Ile (c.946G>A) is very rare (popmax 0.00527%, sas) (gnomAD).

What do computational predictors say about GLA p.Val316Ile (c.946G>A)?

AlphaMissense predicts likely benign (score 0.0762) — an in-silico prediction, not a clinical call.

GLA p.Val316Ile

c.946G>A · rs142217511 · VCV2138662

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00527%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0762	likely benign
REVEL	0.414	indeterminate
SaProt	LLR -4.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	18.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00527% South Asian · 3/56,913 alleles

Filtering AF 0.0014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000688%

Overall 0.00119% 13/1,096,543 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00527%	18,971
Admixed American	0.00217%	45,997
African / African-American	0.00174%	57,626
European (non-Finnish)	0.000895%	111,746

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.Val316Ile
Coding: c.946G>A
MANE Select: NM_000169
dbSNP: rs142217511
Type: single nucleotide variant
Location: chrX:101398423 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 316: a UniProt-annotated variant site (in fabryd); a UniProt-annotated variant site (in fabryd; uncertain significance; decreased enzyme activity); an α-helix

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

Similar variants

GLA p.Val316Ala Uncertain significance ★★ ⚠ same residue
GLA p.Val316Glu Likely pathogenic ★ same residue
GLA p.Val316Gly Likely pathogenic ★ same residue
GLA p.Val316_Asp322del Likely pathogenic ★ same residue
GLA p.Val316fs 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-val316ile (accessed [today's date]).

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