Is PGAM2 p.Pro123Leu (c.368C>T) pathogenic?

PGAM2 p.Pro123Leu (c.368C>T) is classified Uncertain significance in PGAM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-27). AlphaMissense: likely pathogenic (0.9603); Ultra-rare (popmax 0.0105%, nfe); Associated with glycogen storage disease due to phosphoglycerate mutase deficiency.

What condition is associated with PGAM2 p.Pro123Leu (c.368C>T)?

PGAM2 p.Pro123Leu (c.368C>T) is associated with glycogen storage disease due to phosphoglycerate mutase deficiency (ClinVar).

How common is PGAM2 p.Pro123Leu (c.368C>T) in the general population?

PGAM2 p.Pro123Leu (c.368C>T) is ultra-rare (popmax 0.0105%, nfe) (gnomAD).

What do computational predictors say about PGAM2 p.Pro123Leu (c.368C>T)?

AlphaMissense predicts likely pathogenic (score 0.9603) — an in-silico prediction, not a clinical call.

PGAM2 p.Pro123Leu

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

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

c.368C>T · rs372435680 · VCV2321542

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9603 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease due to phosphoglycerate mutase deficiency

Computational evidence

Protein change
AlphaMissense	0.9603	likely pathogenic
REVEL	0.723	pathogenic-leaning
SaProt	LLR -16.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,762 bp · p 0.7 · regional, not allelic
Overall
CADD	28.5	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 0.0105% European (non-Finnish) · 124/1,180,012 alleles

Filtering AF 0.00891% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00842%

Overall 0.00836% 135/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0105%	9,516
East Asian	0.00669%	14,958
Admixed American	0.00333%	30,009
Remaining individualsnot grpmax-eligible	0.0032%	31,254
African / African-American	0.00267%	37,516
South Asian	0.0022%	45,542

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: PGAM2
Protein: p.Pro123Leu
Coding: c.368C>T
MANE Select: NM_001014436 · reported on NM_000290
dbSNP: rs372435680
Type: single nucleotide variant
Location: chr7:44065162 (GRCh38)

Full PGAM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

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

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

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/pgam2-p-pro123leu (accessed [today's date]).

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