Is GLA p.Pro114Leu (c.341C>T) pathogenic?

GLA p.Pro114Leu (c.341C>T) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-24). AlphaMissense: likely benign (0.2514); Very rare (popmax 0.000112%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Pro114Leu (c.341C>T)?

GLA p.Pro114Leu (c.341C>T) is associated with Fabry disease (ClinVar).

How common is GLA p.Pro114Leu (c.341C>T) in the general population?

GLA p.Pro114Leu (c.341C>T) is very rare (popmax 0.000112%, nfe) (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.Pro114Leu (c.341C>T)?

AlphaMissense predicts likely benign (score 0.2514) — an in-silico prediction, not a clinical call.

GLA p.Pro114Leu

c.341C>T · rs1555986247 · VCV1966900

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2514 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.2514	likely benign
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -12.82	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 12	GERP 3.4, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	25.9	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 0.000112% European (non-Finnish) · 1/894,926 alleles

Overall 8.26e-05% 1/1,210,314 alleles · very rare exomes 0/1,097,655 · genomes 1/112,659 · 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.Pro114Leu
Coding: c.341C>T
MANE Select: NM_000169
dbSNP: rs1555986247
Type: single nucleotide variant
Location: chrX:101403839 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 114: a β-strand; a UniProt-annotated variant site (in fabryd)

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

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.Pro114fs Pathogenic ★ same residue
GLA p.Pro114= Likely benign ★ 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-pro114leu (accessed [today's date]).

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