Is GMPPB p.Leu34Phe (c.102G>C) pathogenic?

GMPPB p.Leu34Phe (c.102G>C) is classified Uncertain significance in GMPPB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-12). AlphaMissense: likely pathogenic (0.9071); Absent from gnomAD v4.1; Associated with GMPPB-related disorder.

What condition is associated with GMPPB p.Leu34Phe (c.102G>C)?

GMPPB p.Leu34Phe (c.102G>C) is associated with GMPPB-related disorder (ClinVar).

How common is GMPPB p.Leu34Phe (c.102G>C) in the general population?

GMPPB p.Leu34Phe (c.102G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GMPPB p.Leu34Phe (c.102G>C)?

AlphaMissense predicts likely pathogenic (score 0.9071) — an in-silico prediction, not a clinical call.

GMPPB p.Leu34Phe

c.102G>C · VCV3344960

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9071 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GMPPB-related disorder

Computational evidence

Protein change
AlphaMissense	0.9071	likely pathogenic
REVEL	0.864	moderately pathogenic-leaning
SaProt	LLR -10.73	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 0.51	GERP -1.9, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 1,971 bp · p 0.021 · regional, not allelic
Overall
CADD	22.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GMPPB
Protein: p.Leu34Phe
Coding: c.102G>C
MANE Select: NM_021971
Type: single nucleotide variant
Location: chr3:49723625 (GRCh38)
Gene constraint: LOEUF 1.189 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.33 · 3 PDB
Residue 34: the 'substrate-binding domain' region; an α-helix

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

Disease context

GMPPB-related disorder

Similar variants

GMPPB p.Arg287Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
GMPPB p.Arg287Trp Pathogenic ★★ same condition
GMPPB p.Asp27His Pathogenic/Likely pathogenic ★★ same condition
GMPPB p.Asp334Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
GMPPB p.Ile219Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
GMPPB p.Thr153Ile Pathogenic/Likely pathogenic ★★ same condition
GMPPB p.Val330Ile Pathogenic/Likely pathogenic ★★ ⚠ same condition
GMPPB p.Arg357His Conflicting classifications of pathogenicity ★ ⚠ 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-leu34phe (accessed [today's date]).

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