Is GLA p.Met70Val (c.208A>G) pathogenic?

GLA p.Met70Val (c.208A>G) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.0789); Very rare (popmax 0.000224%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Met70Val (c.208A>G)?

GLA p.Met70Val (c.208A>G) is associated with Fabry disease (ClinVar).

How common is GLA p.Met70Val (c.208A>G) in the general population?

GLA p.Met70Val (c.208A>G) is very rare (popmax 0.000224%, nfe) (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.Met70Val (c.208A>G)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

GLA p.Met70Val

c.208A>G · rs1555986330 · VCV1172250

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.522	indeterminate
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 3.4, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 3,899 bp · p 4.8e-07 · regional, not allelic
Overall
CADD	13.27	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 0.000224% European (non-Finnish) · 2/891,056 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000166% 2/1,206,895 alleles · very rare exomes 2/1,093,143 · genomes 0/113,752 · 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.Met70Val
Coding: c.208A>G
MANE Select: NM_000169
dbSNP: rs1555986330
Type: single nucleotide variant
Location: chrX:101403972 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 70: an α-helix

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)

Similar variants

GLA p.Met70Thr 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
GLA c.194+1G>T Pathogenic ★★ same condition
GLA c.195-1G>C 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-met70val (accessed [today's date]).

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