Is GLA p.Leu68Phe (c.202C>T) pathogenic?

GLA p.Leu68Phe (c.202C>T) is classified Pathogenic/Likely pathogenic in GLA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-09-08). AlphaMissense: ambiguous (0.5159); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Leu68Phe (c.202C>T)?

GLA p.Leu68Phe (c.202C>T) is associated with Cardiovascular phenotype, Fabry disease (ClinVar).

How common is GLA p.Leu68Phe (c.202C>T) in the general population?

GLA p.Leu68Phe (c.202C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Leu68Phe (c.202C>T)?

AlphaMissense predicts ambiguous (score 0.5159) — an in-silico prediction, not a clinical call.

GLA p.Leu68Phe

c.202C>T · rs1928411447 · VCV855220

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5159 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5159	ambiguous
REVEL	0.927	moderately pathogenic-leaning
SaProt	LLR -7.29	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 9.8	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	24.9	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.Leu68Phe
Coding: c.202C>T
MANE Select: NM_000169
dbSNP: rs1928411447
Type: single nucleotide variant
Location: chrX:101403978 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 68: an α-helix; a disulfide bond

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

Also linked: Fabry disease

Similar variants

GLA p.Leu68Pro Likely pathogenic ★ 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-leu68phe (accessed [today's date]).

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