Is GLA p.Arg112Cys (c.334C>T) pathogenic?

GLA p.Arg112Cys (c.334C>T) is classified Pathogenic in GLA (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-09-08). AlphaMissense: ambiguous (0.4129); Absent from gnomAD v4.1; Associated with GLA-related disorder.

What condition is associated with GLA p.Arg112Cys (c.334C>T)?

GLA p.Arg112Cys (c.334C>T) is associated with GLA-related disorder, Fabry disease (ClinVar).

How common is GLA p.Arg112Cys (c.334C>T) in the general population?

GLA p.Arg112Cys (c.334C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Arg112Cys (c.334C>T)?

AlphaMissense predicts ambiguous (score 0.4129) — an in-silico prediction, not a clinical call.

GLA p.Arg112Cys

c.334C>T · rs104894834 · VCV92550

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

ambiguous

0.4129 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

GLA-related disorder

Computational evidence

Protein change
AlphaMissense	0.4129	ambiguous
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -12.07	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
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	29.0	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.Arg112Cys
Coding: c.334C>T
MANE Select: NM_000169
dbSNP: rs104894834
Type: single nucleotide variant
Location: chrX:101403846 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 112: a turn; a UniProt-annotated variant site (in fabryd); a UniProt-annotated variant site (in fabryd; mild)

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

Disease context

GLA-related disorder

Also linked: Fabry disease

Similar variants

GLA p.Arg112His Pathogenic/Likely pathogenic ★★ ⚠ same residue
GLA p.Arg112Leu Pathogenic/Likely pathogenic ★★ same residue
GLA p.Arg112Ser Likely pathogenic ★★ same residue
GLA p.Arg112Gly Likely 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

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-arg112cys (accessed [today's date]).

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