Is BPGM p.Arg90Cys (c.268C>T) pathogenic?

BPGM p.Arg90Cys (c.268C>T) is classified Pathogenic in BPGM (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-12). AlphaMissense: likely pathogenic (0.8212); Ultra-rare (popmax 0.033%, mid); Associated with hemolytic anemia due to diphosphoglycerate mutase deficiency.

What condition is associated with BPGM p.Arg90Cys (c.268C>T)?

BPGM p.Arg90Cys (c.268C>T) is associated with hemolytic anemia due to diphosphoglycerate mutase deficiency (ClinVar).

How common is BPGM p.Arg90Cys (c.268C>T) in the general population?

BPGM p.Arg90Cys (c.268C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about BPGM p.Arg90Cys (c.268C>T)?

AlphaMissense predicts likely pathogenic (score 0.8212) — an in-silico prediction, not a clinical call.

BPGM p.Arg90Cys

Q: How is Hemolytic anemia due to diphosphoglycerate mutase deficiency inherited?

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

c.268C>T · rs121964925 · VCV12091

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8212 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemolytic anemia due to diphosphoglycerate mutase deficiency

Computational evidence

Protein change
AlphaMissense	0.8212	likely pathogenic ✓ concordant with ClinVar
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -14.08	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 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 18 kb · p 0.01 · regional, not allelic
Overall
CADD	32.0	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000372% 6/1,614,080 alleles · ultra-rare exomes 6/1,461,840 · genomes 0/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Finnishnot grpmax-eligible	0.00156%	64,028
European (non-Finnish)	0.000254%	393,332

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: BPGM
Protein: p.Arg90Cys
Coding: c.268C>T
MANE Select: NM_001724
dbSNP: rs121964925
Type: single nucleotide variant
Location: chr7:134661775 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.81 · 17 PDB
Residue 90: a UniProt-annotated variant site (in ecyt8; mutation identified at protein level; marked decrease in synthase and mutase activities; no effect on phosphatase activity); an α-helix; a binding site

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

Disease context

hemolytic anemia due to diphosphoglycerate mutase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hemolytic anemia due to diphosphoglycerate mutase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

BPGM p.Arg90His Pathogenic same residue
BPGM p.Arg154Gln Uncertain significance ★ ⚠ same condition
BPGM p.Arg21His Uncertain significance ★ ⚠ same condition
BPGM p.Arg227Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
BPGM c.601+16A>G Likely benign ★ same condition
BPGM p.Arg62Gln Pathogenic same condition
BPGM p.Arg21fs Pathogenic same condition
BPGM p.Glu176Lys 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/bpgm-p-arg90cys (accessed [today's date]).

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