Is GLA p.Tyr216Phe (c.647A>T) pathogenic?

GLA p.Tyr216Phe (c.647A>T) is classified Uncertain significance in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-08). AlphaMissense: likely benign (0.1387); Absent from gnomAD v4.1; Associated with Fabry disease.

What condition is associated with GLA p.Tyr216Phe (c.647A>T)?

GLA p.Tyr216Phe (c.647A>T) is associated with Fabry disease (ClinVar).

How common is GLA p.Tyr216Phe (c.647A>T) in the general population?

GLA p.Tyr216Phe (c.647A>T) is absent from gnomAD v4.1 (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.Tyr216Phe (c.647A>T)?

AlphaMissense predicts likely benign (score 0.1387) — an in-silico prediction, not a clinical call.

GLA p.Tyr216Phe

c.647A>T · VCV4087449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1387 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.1387	likely benign
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -7.82	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 6.1	GERP 3.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	24.1	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

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.Tyr216Phe
Coding: c.647A>T
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101398939 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 216: a UniProt-annotated variant site (in fabryd); an α-helix

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.Tyr216Cys Pathogenic ★★ same residue
GLA p.Tyr216Ser Uncertain significance ★★ ⚠ same residue
GLA p.Tyr216Ter Pathogenic ★ same residue
GLA p.Tyr216= Likely benign ★ same residue
GLA p.Tyr216fs 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

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-tyr216phe (accessed [today's date]).

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