Is GLA p.Ser238Cys (c.712A>T) pathogenic?

GLA p.Ser238Cys (c.712A>T) is classified Likely pathogenic in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: ambiguous (0.3837); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Ser238Cys (c.712A>T)?

GLA p.Ser238Cys (c.712A>T) is associated with Cardiovascular phenotype (ClinVar).

How common is GLA p.Ser238Cys (c.712A>T) in the general population?

GLA p.Ser238Cys (c.712A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Ser238Cys (c.712A>T)?

AlphaMissense predicts ambiguous (score 0.3837) — an in-silico prediction, not a clinical call.

GLA p.Ser238Cys

c.712A>T · VCV3854126

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3837 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3837	ambiguous
REVEL	0.888	moderately pathogenic-leaning
SaProt	LLR -11.76	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.38 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	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	25.3	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.Ser238Cys
Coding: c.712A>T
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101398874 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 238: an α-helix

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

Similar variants

GLA p.Ser238Asn Pathogenic/Likely pathogenic ★★ ⚠ same residue
GLA p.Ser238= Conflicting classifications of pathogenicity ★ same residue
GLA p.Ser238Arg Uncertain significance ★ ⚠ same residue
GLA p.Ser238Gly Uncertain significance ★ ⚠ same residue
GLA c.802-2A>T Pathogenic/Likely pathogenic ★★ same condition
GLA p.Ala143Pro Pathogenic/Likely pathogenic ★★ same condition
GLA p.Arg112His Pathogenic/Likely pathogenic ★★ ⚠ same condition
GLA p.Arg112Leu 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-ser238cys (accessed [today's date]).

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