Is GLA p.Ser65Ile (c.194G>T) pathogenic?

GLA p.Ser65Ile (c.194G>T) is classified Pathogenic/Likely pathogenic in GLA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-09-08). AlphaMissense: likely pathogenic (0.7343); Absent from gnomAD v4.1; Associated with GLA-related disorder.

What condition is associated with GLA p.Ser65Ile (c.194G>T)?

GLA p.Ser65Ile (c.194G>T) is associated with GLA-related disorder, Fabry disease (ClinVar).

How common is GLA p.Ser65Ile (c.194G>T) in the general population?

GLA p.Ser65Ile (c.194G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Ser65Ile (c.194G>T)?

AlphaMissense predicts likely pathogenic (score 0.7343) — an in-silico prediction, not a clinical call.

GLA p.Ser65Ile

c.194G>T · VCV4087297

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7343 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GLA-related disorder

Computational evidence

Protein change
AlphaMissense	0.7343	likely pathogenic ✓ concordant with ClinVar
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -15.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.91	donor gain · deltas
Pangolin	Δ0.74	loss · gain 0.48 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 3.3, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 3,899 bp · p 4.8e-07 · regional, not allelic
Overall
CADD	38.0	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.Ser65Ile
Coding: c.194G>T
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101407710 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 65: a β-strand; a UniProt-annotated variant site (in fabryd; does not affect enzyme function)

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.Ser65= Likely benign ★★ same residue
GLA p.Ser65Thr Pathogenic ★ ⚠ same residue
GLA p.Ser65Asn Uncertain significance ★ ⚠ same residue
GLA p.Ser65Ala Uncertain significance ★ 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-ser65ile (accessed [today's date]).

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