Is GLA p.Tyr152His (c.454T>C) pathogenic?

GLA p.Tyr152His (c.454T>C) is classified Likely pathogenic in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-08). AlphaMissense: ambiguous (0.3603); Very rare (popmax 0.000112%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Tyr152His (c.454T>C)?

GLA p.Tyr152His (c.454T>C) is associated with Fabry disease (ClinVar).

How common is GLA p.Tyr152His (c.454T>C) in the general population?

GLA p.Tyr152His (c.454T>C) is very rare (popmax 0.000112%, 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.Tyr152His (c.454T>C)?

AlphaMissense predicts ambiguous (score 0.3603) — an in-silico prediction, not a clinical call.

GLA p.Tyr152His

c.454T>C · VCV4087375

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.3603	ambiguous
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -9.91	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.3, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	25.0	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 0.000112% European (non-Finnish) · 1/891,545 alleles

Overall 8.28e-05% 1/1,207,620 alleles · very rare exomes 1/1,093,724 · genomes 0/113,896 · 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.Tyr152His
Coding: c.454T>C
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101401725 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 152: 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.Tyr152Asp Likely pathogenic ★★ same residue
GLA p.Tyr152Ter Pathogenic ★★ same residue
GLA p.Tyr152Phe Uncertain significance ★★ ⚠ same residue
GLA p.Tyr152= Likely benign ★★ same residue
GLA p.Tyr152Cys Likely pathogenic ★ ⚠ same residue
GLA p.Tyr152Ser Likely pathogenic ★ same residue
GLA p.Tyr152_Asp153insTyr Uncertain significance ★ same residue
GLA p.Tyr152del Conflicting classifications of pathogenicity ★ same residue

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-tyr152his (accessed [today's date]).

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