Is GMPPB p.Arg293Pro (c.878G>C) pathogenic?

GMPPB p.Arg293Pro (c.878G>C) is classified Uncertain significance in GMPPB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-09). AlphaMissense: likely benign (0.2252); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with GMPPB p.Arg293Pro (c.878G>C)?

GMPPB p.Arg293Pro (c.878G>C) is associated with Inborn genetic diseases (ClinVar).

How common is GMPPB p.Arg293Pro (c.878G>C) in the general population?

GMPPB p.Arg293Pro (c.878G>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about GMPPB p.Arg293Pro (c.878G>C)?

AlphaMissense predicts likely benign (score 0.2252) — an in-silico prediction, not a clinical call.

GMPPB p.Arg293Pro

c.878G>C · rs748809549 · VCV3100520

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2252 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2252	likely benign
REVEL	0.596	indeterminate
SaProt	LLR -10.34	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.32, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 1,971 bp · p 0.021 · regional, not allelic
Overall
CADD	20.3	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 0.004% African / African-American · 3/74,926 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,470 alleles · very rare

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: GMPPB
Protein: p.Arg293Pro
Coding: c.878G>C
MANE Select: NM_021971
dbSNP: rs748809549
Type: single nucleotide variant
Location: chr3:49722038 (GRCh38)
Gene constraint: LOEUF 1.189 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.33 · 3 PDB
Residue 293: the 'hexapeptide repeat domain' region; a UniProt-annotated variant site (in mddgc14; slight reduction in protein abundance; reduces interaction with gmppb but not with gmppa)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GMPPB p.Arg293Trp Uncertain significance ★★ ⚠ same residue
GMPPB p.Arg293Gln Uncertain significance ★ ⚠ same residue
GMPPB c.951+28G>A Uncertain significance ★★ same condition
GMPPB c.951+32G>A Uncertain significance ★★ same condition
GMPPB c.952-22C>A Uncertain significance ★★ same condition
GMPPB p.Arg311His Uncertain significance ★★ ⚠ same condition
GMPPB p.Arg313His Uncertain significance ★★ ⚠ same condition
GMPPB p.Arg319His Uncertain significance ★★ ⚠ same condition

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/gmppb-p-arg293pro (accessed [today's date]).

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