Is GLA p.Ile64= (c.192C>T) pathogenic?

GLA p.Ile64= (c.192C>T) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-09-08). Very rare (popmax 0.00525%, afr); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Ile64= (c.192C>T)?

GLA p.Ile64= (c.192C>T) is associated with Cardiovascular phenotype, Fabry disease (ClinVar).

How common is GLA p.Ile64= (c.192C>T) in the general population?

GLA p.Ile64= (c.192C>T) is very rare (popmax 0.00525%, afr) (gnomAD).

GLA p.Ile64=

c.192C>T · rs1555987080 · VCV1137628

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00525%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 2.4, phastCons 1
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00525% African / African-American · 3/57,117 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000686%

Overall 0.000498% 6/1,205,492 alleles · very rare exomes 4/1,093,393 · genomes 2/112,099 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00525%	19,039
Admixed American	0.00436%	22,917
Remaining individualsnot grpmax-eligible	0.00211%	47,446

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.Ile64=
Coding: c.192C>T
MANE Select: NM_000169
dbSNP: rs1555987080
Type: single nucleotide variant
Location: chrX:101407712 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 64: a β-strand; 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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Fabry disease

Similar variants

GLA p.Ile64Phe 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-ile64 (accessed [today's date]).

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