Is PGK1 p.Ala331Pro (c.991G>C) pathogenic?

PGK1 p.Ala331Pro (c.991G>C) is classified Uncertain significance in PGK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-20). AlphaMissense: likely pathogenic (0.9952); Very rare (popmax 0.00875%, amr); Associated with glycogen storage disease due to phosphoglycerate kinase 1 deficiency.

What condition is associated with PGK1 p.Ala331Pro (c.991G>C)?

PGK1 p.Ala331Pro (c.991G>C) is associated with glycogen storage disease due to phosphoglycerate kinase 1 deficiency (ClinVar).

How common is PGK1 p.Ala331Pro (c.991G>C) in the general population?

PGK1 p.Ala331Pro (c.991G>C) is very rare (popmax 0.00875%, amr) (gnomAD).

What do computational predictors say about PGK1 p.Ala331Pro (c.991G>C)?

AlphaMissense predicts likely pathogenic (score 0.9952) — an in-silico prediction, not a clinical call.

PGK1 p.Ala331Pro

Q: How is Glycogen storage disease due to phosphoglycerate kinase 1 deficiency inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.991G>C · VCV4079545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00875%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease due to phosphoglycerate kinase 1 deficiency

Computational evidence

Protein change
AlphaMissense	0.9952	likely pathogenic
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -13.79	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 2,583 bp · p 0.28 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00875% Admixed American · 4/45,689 alleles

Filtering AF 0.00294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00177%

Overall 0.000331% 4/1,206,879 alleles · very rare

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: PGK1
Protein: p.Ala331Pro
Coding: c.991G>C
MANE Select: NM_000291
Type: single nucleotide variant
Location: chrX:78124928 (GRCh38)
Structure: AlphaFold pLDDT 96.48 · 30 PDB

Full PGK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glycogen storage disease due to phosphoglycerate kinase 1 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to phosphoglycerate kinase 1 deficiency (Orphanet):

Inheritance: X-linked recessive
Onset: Adolescent, Adult, Childhood

Similar variants

PGK1 p.Asp164Val Pathogenic ★★ same condition
PGK1 p.Ala109Asp Uncertain significance ★★ ⚠ same condition
PGK1 p.Ala296Val Uncertain significance ★★ ⚠ same condition
PGK1 p.Ala55Asp Uncertain significance ★★ ⚠ same condition
PGK1 p.Arg151Gln Uncertain significance ★★ same condition
PGK1 p.Arg330Trp Uncertain significance ★★ ⚠ same condition
PGK1 p.Asn163Ser Uncertain significance ★★ ⚠ same condition
PGK1 p.Asn26Ser Uncertain significance ★★ ⚠ 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/pgk1-p-ala331pro (accessed [today's date]).

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