Is GLA p.Met421Val (c.1261A>G) pathogenic?

GLA p.Met421Val (c.1261A>G) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.0542); Ultra-rare (popmax 0.0157%, afr); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Met421Val (c.1261A>G)?

GLA p.Met421Val (c.1261A>G) is associated with Cardiovascular phenotype, Fabry disease (ClinVar).

How common is GLA p.Met421Val (c.1261A>G) in the general population?

GLA p.Met421Val (c.1261A>G) is ultra-rare (popmax 0.0157%, afr) (gnomAD).

What do computational predictors say about GLA p.Met421Val (c.1261A>G)?

AlphaMissense predicts likely benign (score 0.0542) — an in-silico prediction, not a clinical call.

GLA p.Met421Val

c.1261A>G · rs144060196 · VCV515170

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0542 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0542	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -4.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -2
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	1.153	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 0.0157% African / African-American · 9/57,333 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00602%

Overall 0.000747% 9/1,205,032 alleles · ultra-rare exomes 5/1,092,258 · genomes 4/112,774 · joint denominator

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.Met421Val
Coding: c.1261A>G
MANE Select: NM_000169
dbSNP: rs144060196
Type: single nucleotide variant
Location: chrX:101397838 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 421: 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: Fabry disease

Similar variants

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
GLA c.194+1G>T Pathogenic ★★ same condition
GLA c.195-1G>C Pathogenic ★★ same condition
GLA c.195-1G>T 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-met421val (accessed [today's date]).

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