Is GLA p.Asn320Ser (c.959A>G) pathogenic?

GLA p.Asn320Ser (c.959A>G) is classified Uncertain significance in GLA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely benign (0.0603); Very rare (popmax 0.000112%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with GLA p.Asn320Ser (c.959A>G)?

GLA p.Asn320Ser (c.959A>G) is associated with Cardiovascular phenotype (ClinVar).

How common is GLA p.Asn320Ser (c.959A>G) in the general population?

GLA p.Asn320Ser (c.959A>G) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about GLA p.Asn320Ser (c.959A>G)?

AlphaMissense predicts likely benign (score 0.0603) — an in-silico prediction, not a clinical call.

GLA p.Asn320Ser

c.959A>G · VCV4029996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0603	likely benign
REVEL	0.648	pathogenic-leaning
SaProt	LLR -10.94	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 3.4, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 6,067 bp · p 6.6e-08 · regional, not allelic
Overall
CADD	19.28	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

Grpmax group 0.000112% European (non-Finnish) · 1/894,041 alleles

Overall 8.26e-05% 1/1,209,938 alleles · very rare exomes 1/1,096,569 · genomes 0/113,369 · 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.Asn320Ser
Coding: c.959A>G
MANE Select: NM_000169
Type: single nucleotide variant
Location: chrX:101398410 (GRCh38)
Structure: AlphaFold pLDDT 94.45 · 31 PDB
Residue 320: a UniProt-annotated variant site (in fabryd); a UniProt-annotated variant site (in fabryd; loss of enzyme activity); an α-helix

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

Similar variants

GLA p.Asn320Ile Likely pathogenic ★ same residue
GLA p.Asn320Lys Likely pathogenic ★ same residue
GLA p.Asn320Tyr Likely pathogenic ★ same residue
GLA p.Asn320His Conflicting classifications of pathogenicity ★ ⚠ same residue
GLA c.802-2A>T Pathogenic/Likely pathogenic ★★ same condition
GLA p.Ala143Pro Pathogenic/Likely pathogenic ★★ same condition
GLA p.Arg112His Pathogenic/Likely pathogenic ★★ ⚠ same condition
GLA p.Arg112Leu Pathogenic/Likely 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-asn320ser (accessed [today's date]).

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