Is PGAM2 p.Arg140His (c.419G>A) pathogenic?

PGAM2 p.Arg140His (c.419G>A) is classified Uncertain significance in PGAM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). AlphaMissense: ambiguous (0.3686); Ultra-rare (popmax 0.0102%, nfe); Associated with glycogen storage disease due to phosphoglycerate mutase deficiency.

What condition is associated with PGAM2 p.Arg140His (c.419G>A)?

PGAM2 p.Arg140His (c.419G>A) is associated with glycogen storage disease due to phosphoglycerate mutase deficiency (ClinVar).

How common is PGAM2 p.Arg140His (c.419G>A) in the general population?

PGAM2 p.Arg140His (c.419G>A) is ultra-rare (popmax 0.0102%, nfe) (gnomAD).

What do computational predictors say about PGAM2 p.Arg140His (c.419G>A)?

AlphaMissense predicts ambiguous (score 0.3686) — an in-silico prediction, not a clinical call.

PGAM2 p.Arg140His

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.419G>A · rs757821886 · VCV2173394

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Conditions

glycogen storage disease due to phosphoglycerate mutase deficiency

Computational evidence

Protein change
AlphaMissense	0.3686	ambiguous
REVEL	0.468	indeterminate
SaProt	LLR -10.43	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,762 bp · p 0.7 · regional, not allelic
Overall
CADD	24.3	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 0.0102% European (non-Finnish) · 120/1,179,572 alleles

Filtering AF 0.00868% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00803% 129/1,606,334 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,830
Admixed American	0.00501%	19,947
Remaining individualsnot grpmax-eligible	0.00321%	31,196
South Asian	0.0022%	45,446
Finnishnot grpmax-eligible	0.00174%	57,308
African / African-American	0.00133%	74,922

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.Arg140His
Coding: c.419G>A
MANE Select: NM_001014436 · reported on NM_000290
dbSNP: rs757821886
Type: single nucleotide variant
Location: chr7:44065008 (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-arg140his (accessed [today's date]).

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