Is PGAM2 p.Arg65His (c.194G>A) pathogenic?

PGAM2 p.Arg65His (c.194G>A) is classified Uncertain significance in PGAM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-26). AlphaMissense: likely benign (0.187); Ultra-rare (popmax 0.0214%, afr); Associated with glycogen storage disease due to phosphoglycerate mutase deficiency.

What condition is associated with PGAM2 p.Arg65His (c.194G>A)?

PGAM2 p.Arg65His (c.194G>A) is associated with glycogen storage disease due to phosphoglycerate mutase deficiency (ClinVar).

How common is PGAM2 p.Arg65His (c.194G>A) in the general population?

PGAM2 p.Arg65His (c.194G>A) is ultra-rare (popmax 0.0214%, afr) (gnomAD).

What do computational predictors say about PGAM2 p.Arg65His (c.194G>A)?

AlphaMissense predicts likely benign (score 0.187) — an in-silico prediction, not a clinical call.

PGAM2 p.Arg65His

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.194G>A · rs200420235 · VCV966969

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.187 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glycogen storage disease due to phosphoglycerate mutase deficiency

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.187	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -7.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.6	GERP 1.8, phastCons 0.96
Regional constraint	o/e 0.98	unconstrained · MANE · 2,762 bp · p 0.7 · regional, not allelic
Overall
CADD	17.64	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0214% African / African-American · 16/74,914 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00279% 45/1,613,464 alleles · ultra-rare exomes 32/1,461,290 · genomes 13/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0214%	4,682
European (non-Finnish)	0.0022%	45,386
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,480
South Asian	0.0011%	91,088

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.Arg65His
Coding: c.194G>A
MANE Select: NM_000290
dbSNP: rs200420235
Type: single nucleotide variant
Location: chr7:44065336 (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-arg65his (accessed [today's date]).

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