Is GLA p.Trp24Arg (c.70T>A) pathogenic?

GLA p.Trp24Arg (c.70T>A) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.1493); Very rare (popmax 0.00295%, eas); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Trp24Arg (c.70T>A)?

GLA p.Trp24Arg (c.70T>A) is associated with Cardiovascular phenotype, cardiomyopathy, Fabry disease (ClinVar).

How common is GLA p.Trp24Arg (c.70T>A) in the general population?

GLA p.Trp24Arg (c.70T>A) is very rare (popmax 0.00295%, eas) (gnomAD).

What do computational predictors say about GLA p.Trp24Arg (c.70T>A)?

AlphaMissense predicts likely benign (score 0.1493) — an in-silico prediction, not a clinical call.

GLA p.Trp24Arg

c.70T>A · rs397515871 · VCV42459

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1493 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00295%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1493	likely benign
REVEL	0.403	indeterminate
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.1, phastCons 0.038
Regional constraint	o/e 0.93	unconstrained · MANE · 123 bp · p 0.7 · regional, not allelic
Overall
CADD	10.61	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 0.00295% East Asian · 1/33,851 alleles

Overall 0.000365% 4/1,097,274 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0063%	15,874
East Asiangrpmax	0.00295%	33,851

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Trp24Arg
Coding: c.70T>A
MANE Select: NM_000169
dbSNP: rs397515871
Type: single nucleotide variant
Location: chrX:101407834 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB

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.Trp24Ter Pathogenic ★★ same residue
GLA p.Trp24Cys Uncertain significance ★ ⚠ same residue
GLA p.Trp24Gly 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-trp24arg (accessed [today's date]).

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