Is MPI p.Glu331Ala (c.992A>C) pathogenic?

MPI p.Glu331Ala (c.992A>C) is classified Uncertain significance in MPI (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.1101); Ultra-rare (popmax 0.0117%, amr); Associated with Inborn genetic diseases.

What condition is associated with MPI p.Glu331Ala (c.992A>C)?

MPI p.Glu331Ala (c.992A>C) is associated with Inborn genetic diseases, MPI-congenital disorder of glycosylation (ClinVar).

How common is MPI p.Glu331Ala (c.992A>C) in the general population?

MPI p.Glu331Ala (c.992A>C) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about MPI p.Glu331Ala (c.992A>C)?

AlphaMissense predicts likely benign (score 0.1101) — an in-silico prediction, not a clinical call.

MPI p.Glu331Ala

c.992A>C · rs1223295146 · VCV1030556

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1101 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1101	likely benign
REVEL	0.254	benign-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,653 bp · p 0.66 · regional, not allelic
Overall
CADD	19.18	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 0.0117% Admixed American · 7/59,974 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000434% 7/1,614,050 alleles · ultra-rare exomes 6/1,461,886 · genomes 1/152,164 · 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: MPI
Protein: p.Glu331Ala
Coding: c.992A>C
MANE Select: NM_002435
dbSNP: rs1223295146
Type: single nucleotide variant
Location: chr15:74897158 (GRCh38)
Gene constraint: LOEUF 1.04 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.50

Full MPI 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

Also linked: MPI-congenital disorder of glycosylation

Similar variants

MPI p.Glu331Gly Uncertain significance ★ ⚠ same residue
MPI p.Glu331= Likely benign ★ same residue
MPI p.Glu331fs Pathogenic/Likely pathogenic ★★ same residue
MPI c.145-1G>C Likely pathogenic ★★ same condition
MPI c.16+2T>C Likely pathogenic ★★ same condition
MPI c.488-1G>C Pathogenic/Likely pathogenic ★★ same condition
MPI c.488-2A>G Likely pathogenic ★★ same condition
MPI c.844+1G>A Likely pathogenic ★★ 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/mpi-p-glu331ala (accessed [today's date]).

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