Is GLA p.Leu206Phe (c.616C>T) pathogenic?

GLA p.Leu206Phe (c.616C>T) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-08-13). AlphaMissense: likely benign (0.1202); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Leu206Phe (c.616C>T)?

GLA p.Leu206Phe (c.616C>T) is associated with Cardiovascular phenotype, Fabry disease, familial hypertrophic cardiomyopathy (ClinVar).

How common is GLA p.Leu206Phe (c.616C>T) in the general population?

GLA p.Leu206Phe (c.616C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Leu206Phe (c.616C>T)?

AlphaMissense predicts likely benign (score 0.1202) — an in-silico prediction, not a clinical call.

GLA p.Leu206Phe

c.616C>T · rs730880448 · VCV520522

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1202 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1202	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -3.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6.5	GERP 0.86, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	17.58	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Leu206Phe
Coding: c.616C>T
MANE Select: NM_000169
dbSNP: rs730880448
Type: single nucleotide variant
Location: chrX:101400689 (GRCh38)

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 familial hypertrophic cardiomyopathy

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-leu206phe (accessed [today's date]).

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