Is GLA p.Ile270Phe (c.808A>T) pathogenic?

GLA p.Ile270Phe (c.808A>T) is classified Uncertain significance in GLA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-07). AlphaMissense: ambiguous (0.396); Absent from gnomAD v4.1.

How common is GLA p.Ile270Phe (c.808A>T) in the general population?

GLA p.Ile270Phe (c.808A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GLA p.Ile270Phe (c.808A>T)?

AlphaMissense predicts ambiguous (score 0.396) — an in-silico prediction, not a clinical call.

GLA p.Ile270Phe

c.808A>T · rs1569303099 · VCV594189

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.396 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.396	ambiguous
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -13.14	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	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	26.6	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.Ile270Phe
Coding: c.808A>T
MANE Select: NM_000169
dbSNP: rs1569303099
Type: single nucleotide variant
Location: chrX:101398561 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB

Full GLA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GLA p.Ile270Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
GLA p.Ile270Met Likely pathogenic ★ ⚠ same residue
GLA p.Ile270= Uncertain significance same residue
GLA p.Ile270fs Pathogenic ★ same residue
GLA c.1000-10G>A Likely pathogenic ★★ same type
GLA c.1000-1G>A Pathogenic ★★ same type
GLA c.1000-1G>C Pathogenic ★★ same type
GLA c.1023A>C Pathogenic/Likely pathogenic ★★ ⚠ same type

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-ile270phe (accessed [today's date]).

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