Is GLA p.Asp266Val (c.797A>T) pathogenic?

GLA p.Asp266Val (c.797A>T) is classified Pathogenic in GLA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-09-08). AlphaMissense: likely pathogenic (0.9727); Very rare (popmax 0.00175%, afr); Associated with Fabry disease.

What condition is associated with GLA p.Asp266Val (c.797A>T)?

GLA p.Asp266Val (c.797A>T) is associated with Fabry disease (ClinVar).

How common is GLA p.Asp266Val (c.797A>T) in the general population?

GLA p.Asp266Val (c.797A>T) is very rare (popmax 0.00175%, afr) (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.Asp266Val (c.797A>T)?

AlphaMissense predicts likely pathogenic (score 0.9727) — an in-silico prediction, not a clinical call.

GLA p.Asp266Val

c.797A>T · rs28935487 · VCV10735

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.9727	likely pathogenic ✓ concordant with ClinVar · top 2% in GLA
REVEL	0.974	strongly pathogenic-leaning
SaProt	LLR -14.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 3.4, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	28.3	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 0.00175% African / African-American · 1/57,168 alleles

Overall 0.000894% 1/111,873 alleles · very rare

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.Asp266Val
Coding: c.797A>T
MANE Select: NM_000169
dbSNP: rs28935487
Type: single nucleotide variant
Location: chrX:101398789 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 266: a UniProt-annotated variant site (in fabryd)

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.Asp266Asn Pathogenic ★★ same residue
GLA p.Asp266Glu Pathogenic ★ same residue
GLA p.Asp266Gly Likely pathogenic ★ same residue
GLA p.Asp266Tyr Pathogenic ★ same residue
GLA p.Asp266Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
GLA p.Asp266His Conflicting classifications of pathogenicity ★ ⚠ same residue
GLA p.Asp266= Likely benign ★ same residue
GLA c.1000-10G>A Likely 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-asp266val (accessed [today's date]).

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