Is GLA p.Gln416Pro (c.1247A>C) pathogenic?

GLA p.Gln416Pro (c.1247A>C) is classified Conflicting classifications of pathogenicity in GLA (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-09-08). AlphaMissense: ambiguous (0.4787); Absent from gnomAD v4.1; Associated with Fabry disease.

What condition is associated with GLA p.Gln416Pro (c.1247A>C)?

GLA p.Gln416Pro (c.1247A>C) is associated with Fabry disease (ClinVar).

How common is GLA p.Gln416Pro (c.1247A>C) in the general population?

GLA p.Gln416Pro (c.1247A>C) 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.Gln416Pro (c.1247A>C)?

AlphaMissense predicts ambiguous (score 0.4787) — an in-silico prediction, not a clinical call.

GLA p.Gln416Pro

c.1247A>C · rs398123200 · VCV92540

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4787 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Fabry disease

Computational evidence

Protein change
AlphaMissense	0.4787	ambiguous
REVEL	0.55	indeterminate
SaProt	LLR -11.81	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -2.1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	13.69	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.Gln416Pro
Coding: c.1247A>C
MANE Select: NM_000169
dbSNP: rs398123200
Type: single nucleotide variant
Location: chrX:101397852 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 416: a β-strand

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.Gln416Ter Pathogenic ★★ same residue
GLA p.Gln416Arg Uncertain significance ★ ⚠ 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

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-gln416pro (accessed [today's date]).

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