Is GLA p.Arg392Thr (c.1175G>C) pathogenic?

GLA p.Arg392Thr (c.1175G>C) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-14). AlphaMissense: likely benign (0.0781); Very rare (popmax 0.00877%, sas); Associated with Fabry disease.

What condition is associated with GLA p.Arg392Thr (c.1175G>C)?

GLA p.Arg392Thr (c.1175G>C) is associated with Fabry disease (ClinVar).

How common is GLA p.Arg392Thr (c.1175G>C) in the general population?

GLA p.Arg392Thr (c.1175G>C) is very rare (popmax 0.00877%, sas) (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.Arg392Thr (c.1175G>C)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

GLA p.Arg392Thr

c.1175G>C · rs782756052 · VCV524212

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00877%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -2.6	GERP -6.4
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	0.862	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00877% South Asian · 5/57,015 alleles

Filtering AF 0.00339% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00216%

Overall 0.000578% 7/1,211,048 alleles · very rare exomes 7/1,097,078 · genomes 0/113,970 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00877%	11,403
European (non-Finnish)	0.000224%	447,277

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GLA
Protein: p.Arg392Thr
Coding: c.1175G>C
MANE Select: NM_000169
dbSNP: rs782756052
Type: single nucleotide variant
Location: chrX:101397924 (GRCh38)

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)

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-arg392thr (accessed [today's date]).

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