Is GLA p.Cys172Arg (c.514T>C) pathogenic?

GLA p.Cys172Arg (c.514T>C) is classified Pathogenic/Likely pathogenic in GLA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-09-08). AlphaMissense: likely pathogenic (0.9429); Absent from gnomAD v4.1; Associated with Fabry disease.

What condition is associated with GLA p.Cys172Arg (c.514T>C)?

GLA p.Cys172Arg (c.514T>C) is associated with Fabry disease (ClinVar).

How common is GLA p.Cys172Arg (c.514T>C) in the general population?

GLA p.Cys172Arg (c.514T>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.Cys172Arg (c.514T>C)?

AlphaMissense predicts likely pathogenic (score 0.9429) — an in-silico prediction, not a clinical call.

GLA p.Cys172Arg

c.514T>C · rs2520895194 · VCV2737318

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9429 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.9429	likely pathogenic ✓ concordant with ClinVar · top 5% in GLA
REVEL	0.979	strongly pathogenic-leaning
SaProt	LLR -15.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.74 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	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	26.2	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.Cys172Arg
Coding: c.514T>C
MANE Select: NM_000169
dbSNP: rs2520895194
Type: single nucleotide variant
Location: chrX:101401665 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 172: a disulfide bond; 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.Cys172Gly Pathogenic ★★ same residue
GLA p.Cys172Tyr Pathogenic ★★ same residue
GLA p.Cys172Phe Pathogenic ★ same residue
GLA p.Cys172Ser Likely pathogenic ★ same residue
GLA p.Cys172Trp 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-cys172arg (accessed [today's date]).

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