Is GLA p.Leu206Val (c.616C>G) pathogenic?

GLA p.Leu206Val (c.616C>G) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-09-08). AlphaMissense: likely benign (0.2003); Very rare (popmax 0.00354%, afr); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Leu206Val (c.616C>G)?

GLA p.Leu206Val (c.616C>G) is associated with Cardiovascular phenotype, Fabry disease (ClinVar).

How common is GLA p.Leu206Val (c.616C>G) in the general population?

GLA p.Leu206Val (c.616C>G) is very rare (popmax 0.00354%, afr) (gnomAD).

What do computational predictors say about GLA p.Leu206Val (c.616C>G)?

AlphaMissense predicts likely benign (score 0.2003) — an in-silico prediction, not a clinical call.

GLA p.Leu206Val

c.616C>G · rs730880448 · VCV180839

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2003 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00354%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2003	likely benign
REVEL	0.59	indeterminate
SaProt	LLR -4.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	14.66	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

Grpmax group 0.00354% African / African-American · 2/56,464 alleles

Filtering AF 0.000587% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00022%

Overall 0.00017% 2/1,175,605 alleles · very rare exomes 1/1,063,893 · genomes 1/111,712 · 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.Leu206Val
Coding: c.616C>G
MANE Select: NM_000169
dbSNP: rs730880448
Type: single nucleotide variant
Location: chrX:101400689 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 206: a UniProt-annotated variant site (in fabryd); an α-helix; a binding site

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.Leu206Pro 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-leu206val (accessed [today's date]).

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