Is GLA p.Ser235Cys (c.704C>G) pathogenic?

GLA p.Ser235Cys (c.704C>G) is classified Pathogenic/Likely pathogenic in GLA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.2674); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Ser235Cys (c.704C>G)?

GLA p.Ser235Cys (c.704C>G) is associated with Cardiovascular phenotype, Fabry disease (ClinVar).

How common is GLA p.Ser235Cys (c.704C>G) in the general population?

GLA p.Ser235Cys (c.704C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Ser235Cys (c.704C>G)?

AlphaMissense predicts likely benign (score 0.2674) — an in-silico prediction, not a clinical call.

GLA p.Ser235Cys

c.704C>G · rs797044746 · VCV197637

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2674 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2674	likely benign ⚠ discordant with ClinVar
REVEL	0.925	moderately pathogenic-leaning
SaProt	LLR -12.35	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 3.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	26.5	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.Ser235Cys
Coding: c.704C>G
MANE Select: NM_000169
dbSNP: rs797044746
Type: single nucleotide variant
Location: chrX:101398882 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 235: a UniProt-annotated variant site (in fabryd)

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

Disease context

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

Also linked: Fabry disease

Similar variants

GLA p.Ser235= Likely benign ★★ same residue
GLA p.Ser235Phe Pathogenic ★ same residue
GLA p.Ser235Tyr 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

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-ser235cys (accessed [today's date]).

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