Is GLA p.Met76Val (c.226A>G) pathogenic?

GLA p.Met76Val (c.226A>G) is classified Uncertain significance in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-17). AlphaMissense: likely benign (0.1718); Absent from gnomAD v4.1.

How common is GLA p.Met76Val (c.226A>G) in the general population?

GLA p.Met76Val (c.226A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Met76Val (c.226A>G)?

AlphaMissense predicts likely benign (score 0.1718) — an in-silico prediction, not a clinical call.

GLA p.Met76Val

c.226A>G · VCV4078776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1718 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1718	likely benign
REVEL	0.724	pathogenic-leaning
SaProt	LLR -11.35	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 5	GERP -0.62, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 3,899 bp · p 4.8e-07 · regional, not allelic
Overall
CADD	19.09	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.Met76Val
Coding: c.226A>G
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101403954 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 76: an α-helix

Full GLA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GLA p.Met76Ile Uncertain significance ★★ ⚠ same residue
GLA p.Met76Arg Likely pathogenic ★ same residue
GLA p.Met76Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
GLA c.1000-10G>A Likely pathogenic ★★ same type
GLA c.1000-1G>A Pathogenic ★★ same type
GLA c.1000-1G>C Pathogenic ★★ same type
GLA c.1023A>C Pathogenic/Likely pathogenic ★★ ⚠ same type
GLA c.194+1G>A Pathogenic ★★ same type

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-met76val (accessed [today's date]).

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