Is GLA p.Pro305Leu (c.914C>T) pathogenic?

GLA p.Pro305Leu (c.914C>T) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-14). AlphaMissense: likely benign (0.0654); Very rare (popmax 0.000561%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Pro305Leu (c.914C>T)?

GLA p.Pro305Leu (c.914C>T) is associated with Fabry disease (ClinVar).

How common is GLA p.Pro305Leu (c.914C>T) in the general population?

GLA p.Pro305Leu (c.914C>T) is very rare (popmax 0.000561%, 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.Pro305Leu (c.914C>T)?

AlphaMissense predicts likely benign (score 0.0654) — an in-silico prediction, not a clinical call.

GLA p.Pro305Leu

c.914C>T · rs1465021475 · VCV629461

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000561%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Fabry disease

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0654	likely benign
REVEL	0.521	indeterminate
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.4	GERP 1.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	20.5	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 0.000561% European (non-Finnish) · 5/890,804 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000415% 5/1,204,953 alleles · very rare exomes 4/1,093,288 · genomes 1/111,665 · 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.Pro305Leu
Coding: c.914C>T
MANE Select: NM_000169
dbSNP: rs1465021475
Type: single nucleotide variant
Location: chrX:101398455 (GRCh38)

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)

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-pro305leu (accessed [today's date]).

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