Is GLA p.Ala348Pro (c.1042G>C) pathogenic?

GLA p.Ala348Pro (c.1042G>C) is classified Likely pathogenic in GLA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-09-08). AlphaMissense: ambiguous (0.3988); Absent from gnomAD v4.1; Associated with Fabry disease.

What condition is associated with GLA p.Ala348Pro (c.1042G>C)?

GLA p.Ala348Pro (c.1042G>C) is associated with Fabry disease, familial hypertrophic cardiomyopathy (ClinVar).

How common is GLA p.Ala348Pro (c.1042G>C) in the general population?

GLA p.Ala348Pro (c.1042G>C) is absent from gnomAD v4.1 (gnomAD).

How is Fabry disease inherited?

Typically X-linked dominant, X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GLA p.Ala348Pro (c.1042G>C)?

AlphaMissense predicts ambiguous (score 0.3988) — an in-silico prediction, not a clinical call.

GLA p.Ala348Pro

c.1042G>C · rs1603037717 · VCV684856

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3988 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.3988	ambiguous
REVEL	0.689	pathogenic-leaning
SaProt	LLR -11.26	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.78	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 1.7	GERP 1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	19.57	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: GLA
Protein: p.Ala348Pro
Coding: c.1042G>C
MANE Select: NM_000169
dbSNP: rs1603037717
Type: single nucleotide variant
Location: chrX:101398057 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB

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

Disease context

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

Also linked: familial hypertrophic cardiomyopathy

For Fabry disease (Orphanet):

Inheritance: X-linked dominant, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

GLA p.Ala348Asp Uncertain significance ★ ⚠ same residue
GLA p.Ala348fs 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
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

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-ala348pro (accessed [today's date]).

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