Is GLA p.Leu331Phe (c.991C>T) pathogenic?

GLA p.Leu331Phe (c.991C>T) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-10). AlphaMissense: likely benign (0.0981); Very rare (popmax 0.00113%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Leu331Phe (c.991C>T)?

GLA p.Leu331Phe (c.991C>T) is associated with Cardiovascular phenotype, Fabry disease (ClinVar).

How common is GLA p.Leu331Phe (c.991C>T) in the general population?

GLA p.Leu331Phe (c.991C>T) is very rare (popmax 0.00113%, nfe) (gnomAD).

What do computational predictors say about GLA p.Leu331Phe (c.991C>T)?

AlphaMissense predicts likely benign (score 0.0981) — an in-silico prediction, not a clinical call.

GLA p.Leu331Phe

c.991C>T · rs730880437 · VCV180828

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0981	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -8.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.46 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.9	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	20.1	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 0.00113% European (non-Finnish) · 10/881,641 alleles

Filtering AF 0.000574% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000418%

Overall 0.000837% 10/1,194,896 alleles · very rare exomes 8/1,083,157 · genomes 2/111,739 · 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.Leu331Phe
Coding: c.991C>T
MANE Select: NM_000169
dbSNP: rs730880437
Type: single nucleotide variant
Location: chrX:101398378 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 331: a β-strand

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.Leu331Ile Uncertain significance ★ ⚠ 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
GLA c.1023A>C Pathogenic/Likely pathogenic ★★ ⚠ same condition
GLA c.194+1G>A Pathogenic ★★ same condition
GLA c.194+1G>T Pathogenic ★★ same condition
GLA c.195-1G>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-leu331phe (accessed [today's date]).

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