Is GLA p.Val164Ala (c.491T>C) pathogenic?

GLA p.Val164Ala (c.491T>C) is classified Uncertain significance in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-13). AlphaMissense: ambiguous (0.4191); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Val164Ala (c.491T>C)?

GLA p.Val164Ala (c.491T>C) is associated with Cardiovascular phenotype (ClinVar).

How common is GLA p.Val164Ala (c.491T>C) in the general population?

GLA p.Val164Ala (c.491T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Val164Ala (c.491T>C)?

AlphaMissense predicts ambiguous (score 0.4191) — an in-silico prediction, not a clinical call.

GLA p.Val164Ala

c.491T>C · rs2520895621 · VCV1744116

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4191 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4191	ambiguous
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -13.51	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	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	25.7	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.Val164Ala
Coding: c.491T>C
MANE Select: NM_000169
dbSNP: rs2520895621
Type: single nucleotide variant
Location: chrX:101401688 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 164: a UniProt-annotated variant site (in fabryd; loss of enzyme activity); a UniProt-annotated variant site (in fabryd; uncertain significance; decreased enzyme activity)

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

Similar variants

GLA p.Val164Ile Uncertain significance ★★ ⚠ same residue
GLA p.Val164Leu Uncertain significance ★★ ⚠ same residue
GLA p.Val164Gly Pathogenic ★ same residue
GLA c.802-2A>T Pathogenic/Likely pathogenic ★★ same condition
GLA p.Ala143Pro Pathogenic/Likely pathogenic ★★ same condition
GLA p.Arg112His Pathogenic/Likely pathogenic ★★ ⚠ same condition
GLA p.Arg112Leu Pathogenic/Likely pathogenic ★★ same condition
GLA p.Arg301Gln 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-val164ala (accessed [today's date]).

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