Is GLA p.Leu21Pro (c.62T>C) pathogenic?

GLA p.Leu21Pro (c.62T>C) is classified Likely pathogenic in GLA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.1024); Very rare (popmax 0.000112%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Leu21Pro (c.62T>C)?

GLA p.Leu21Pro (c.62T>C) is associated with Fabry disease (ClinVar).

How common is GLA p.Leu21Pro (c.62T>C) in the general population?

GLA p.Leu21Pro (c.62T>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.Leu21Pro (c.62T>C)?

AlphaMissense predicts likely benign (score 0.1024) — an in-silico prediction, not a clinical call.

GLA p.Leu21Pro

c.62T>C · rs869312135 · VCV217374

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1024 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.1024	likely benign ⚠ discordant with ClinVar
REVEL	0.682	pathogenic-leaning
SaProt	LLR -10.27	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 3.3, phastCons 0.7
Regional constraint	o/e 0.93	unconstrained · MANE · 123 bp · p 0.7 · regional, not allelic
Overall
CADD	21.3	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 0.000112% European (non-Finnish) · 1/894,819 alleles

Overall 0.000892% 1/112,146 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.Leu21Pro
Coding: c.62T>C
MANE Select: NM_000169
dbSNP: rs869312135
Type: single nucleotide variant
Location: chrX:101407842 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 21: a UniProt-annotated variant site (in fabryd; loss of enzyme activity)

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.Leu21Val Uncertain significance ★★ ⚠ same residue
GLA p.Leu21Arg Likely pathogenic ★ ⚠ same residue
GLA p.Leu21Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
GLA p.Leu21= Likely benign ★ 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

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-leu21pro (accessed [today's date]).

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