Is GLA p.Leu106Phe (c.316C>T) pathogenic?

GLA p.Leu106Phe (c.316C>T) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-09-08). AlphaMissense: likely pathogenic (0.5779); Very rare (popmax 0.000335%, nfe); Associated with Fabry disease.

What condition is associated with GLA p.Leu106Phe (c.316C>T)?

GLA p.Leu106Phe (c.316C>T) is associated with Fabry disease (ClinVar).

How common is GLA p.Leu106Phe (c.316C>T) in the general population?

GLA p.Leu106Phe (c.316C>T) is very rare (popmax 0.000335%, 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.Leu106Phe (c.316C>T)?

AlphaMissense predicts likely pathogenic (score 0.5779) — an in-silico prediction, not a clinical call.

GLA p.Leu106Phe

c.316C>T · rs1178979608 · VCV2432130

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5779 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000335%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.5779	likely pathogenic
REVEL	0.821	moderately pathogenic-leaning
SaProt	LLR -11.94	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	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	24.0	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 0.000335% European (non-Finnish) · 3/894,782 alleles

Filtering AF 8.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.5e-05%

Overall 0.000248% 3/1,210,297 alleles · very rare exomes 2/1,097,474 · genomes 1/112,823 · 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.Leu106Phe
Coding: c.316C>T
MANE Select: NM_000169
dbSNP: rs1178979608
Type: single nucleotide variant
Location: chrX:101403864 (GRCh38)

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)

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-leu106phe (accessed [today's date]).

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