Is MPI p.Pro4Ser (c.10C>T) pathogenic?

MPI p.Pro4Ser (c.10C>T) is classified Conflicting classifications of pathogenicity in MPI (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1151); Low-frequency (popmax 2.35%, mid); Associated with MPI-congenital disorder of glycosylation.

What condition is associated with MPI p.Pro4Ser (c.10C>T)?

MPI p.Pro4Ser (c.10C>T) is associated with MPI-congenital disorder of glycosylation (ClinVar).

How common is MPI p.Pro4Ser (c.10C>T) in the general population?

MPI p.Pro4Ser (c.10C>T) is low-frequency (popmax 2.35%, mid) (gnomAD).

How is MPI-CDG inherited?

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

What do computational predictors say about MPI p.Pro4Ser (c.10C>T)?

AlphaMissense predicts likely benign (score 0.1151) — an in-silico prediction, not a clinical call.

MPI p.Pro4Ser

c.10C>T · rs143982014 · VCV282926

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1151 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.35%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

MPI-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.1151	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP 0.94
Regional constraint	o/e 0.98	unconstrained · MANE · 7,653 bp · p 0.66 · regional, not allelic
Overall
CADD	14.9	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 2.35% Middle Eastern · 139/5,922 alleles

Filtering AF 2.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.91%

Overall 0.141% 2,262/1,607,936 alleles · low-frequency exomes 2,051/1,455,616 · genomes 211/152,320 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.35%	43
Ashkenazi Jewishnot grpmax-eligible	1.14%	88
Admixed American	0.328%	305
Remaining individualsnot grpmax-eligible	0.307%	325
South Asian	0.12%	835
European (non-Finnish)	0.106%	945
African / African-American	0.052%	1,924
East Asian	0.00223%	44,858

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.Pro4Ser
Coding: c.10C>T
MANE Select: NM_002435
dbSNP: rs143982014
Type: single nucleotide variant
Location: chr15:74890083 (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

MPI-congenital disorder of glycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MPI-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

MPI p.Pro4= Uncertain significance same residue
MPI p.Pro4fs 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
MPI c.845-2A>G 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-pro4ser (accessed [today's date]).

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