Is PGM2 p.Arg366Cys (c.1096C>T) pathogenic?

PGM2 p.Arg366Cys (c.1096C>T) is classified Uncertain significance in PGM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-11). AlphaMissense: likely benign (0.092); Ultra-rare (popmax 0.0867%, afr).

How common is PGM2 p.Arg366Cys (c.1096C>T) in the general population?

PGM2 p.Arg366Cys (c.1096C>T) is ultra-rare (popmax 0.0867%, afr) (gnomAD).

What do computational predictors say about PGM2 p.Arg366Cys (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.092) — an in-silico prediction, not a clinical call.

PGM2 p.Arg366Cys

c.1096C>T · rs151106378 · VCV2351370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.092 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0867%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.092	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -6.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.19, phastCons 0.85
Regional constraint	o/e 0.97	unconstrained · MANE · 17 kb · p 0.53 · regional, not allelic
Overall
CADD	24.3	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 0.0867% African / African-American · 65/74,976 alleles

Filtering AF 0.0698% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0636%

Overall 0.00589% 95/1,613,176 alleles · ultra-rare exomes 61/1,461,030 · genomes 34/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0867%	1,153
Remaining individualsnot grpmax-eligible	0.0112%	8,925
Admixed American	0.00667%	15,002
European (non-Finnish)	0.00161%	62,066

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: PGM2
Protein: p.Arg366Cys
Coding: c.1096C>T
MANE Select: NM_018290
dbSNP: rs151106378
Type: single nucleotide variant
Location: chr4:37847019 (GRCh38)
Gene constraint: LOEUF 1.172 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.60

Full PGM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PGM2 p.Asp322= Benign ★★ same type
PGM2 p.Ala107Thr Uncertain significance ★ ⚠ same type
PGM2 p.Ala121Val Uncertain significance ★ ⚠ same type
PGM2 p.Ala124Thr Uncertain significance ★ ⚠ same type
PGM2 p.Ala277Val Uncertain significance ★ ⚠ same type
PGM2 p.Ala2Gly Uncertain significance ★ ⚠ same type
PGM2 p.Ala310Asp Uncertain significance ★ ⚠ same type
PGM2 p.Ala315Asp Uncertain significance ★ ⚠ same type

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/pgm2-p-arg366cys (accessed [today's date]).

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