Is GLA p.Arg118Cys (c.352C>T) pathogenic?

GLA p.Arg118Cys (c.352C>T) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 28 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.1053); Ultra-rare (popmax 0.0764%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Arg118Cys (c.352C>T)?

GLA p.Arg118Cys (c.352C>T) is associated with Cardiovascular phenotype, cardiomyopathy, Fabry disease (ClinVar).

How common is GLA p.Arg118Cys (c.352C>T) in the general population?

GLA p.Arg118Cys (c.352C>T) is ultra-rare (popmax 0.0764%, nfe) (gnomAD).

What do computational predictors say about GLA p.Arg118Cys (c.352C>T)?

AlphaMissense predicts likely benign (score 0.1053) — an in-silico prediction, not a clinical call.

GLA p.Arg118Cys

c.352C>T · rs148158093 · VCV42454

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 28 submitters

AlphaMissense

likely benign

0.1053 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0764%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1053	likely benign
REVEL	0.688	pathogenic-leaning
SaProt	LLR -12.07	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	23.6	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

Grpmax group 0.0764% European (non-Finnish) · 683/894,088 alleles

Filtering AF 0.0716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0697%

Overall 0.0605% 732/1,209,304 alleles · ultra-rare exomes 687/1,096,759 · genomes 45/112,545 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0764%	1,309
Remaining individualsnot grpmax-eligible	0.0568%	1,762
Admixed American	0.0262%	3,820
African / African-American	0.0157%	6,371
Finnishnot grpmax-eligible	0.00214%	46,693

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.Arg118Cys
Coding: c.352C>T
MANE Select: NM_000169
dbSNP: rs148158093
Type: single nucleotide variant
Location: chrX:101403828 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 118: 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

Also linked: cardiomyopathy Fabry disease

Similar variants

GLA p.Arg118Gly Uncertain significance ★ ⚠ same residue
GLA p.Arg118His Conflicting classifications of pathogenicity ★ ⚠ same residue
GLA p.Arg118Ser 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
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-arg118cys (accessed [today's date]).

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