Is GMPPB p.His346Pro (c.1037A>C) pathogenic?

GMPPB p.His346Pro (c.1037A>C) is classified Uncertain significance in GMPPB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.9313); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with GMPPB p.His346Pro (c.1037A>C)?

GMPPB p.His346Pro (c.1037A>C) is associated with Inborn genetic diseases (ClinVar).

How common is GMPPB p.His346Pro (c.1037A>C) in the general population?

GMPPB p.His346Pro (c.1037A>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about GMPPB p.His346Pro (c.1037A>C)?

AlphaMissense predicts likely pathogenic (score 0.9313) — an in-silico prediction, not a clinical call.

GMPPB p.His346Pro

c.1037A>C · rs1472157050 · VCV3253403

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9313 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9313	likely pathogenic
REVEL	0.871	moderately pathogenic-leaning
SaProt	LLR -16.03	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 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 1,971 bp · p 0.021 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.004% African / African-American · 3/74,924 alleles

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

Overall 0.000186% 3/1,611,862 alleles · very rare exomes 0/1,459,656 · genomes 3/152,206 · joint denominator

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.His346Pro
Coding: c.1037A>C
MANE Select: NM_021971
dbSNP: rs1472157050
Type: single nucleotide variant
Location: chr3:49721798 (GRCh38)
Gene constraint: LOEUF 1.189 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.33 · 3 PDB
Residue 346: the 'hexapeptide repeat domain' region

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.His346Tyr 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
GMPPB p.Asn271Ser 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-his346pro (accessed [today's date]).

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