Is MPI p.Pro126= (c.378G>A) pathogenic?

MPI p.Pro126= (c.378G>A) is classified Conflicting classifications of pathogenicity in MPI (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-28). Ultra-rare (popmax 0.032%, afr); Associated with MPI-congenital disorder of glycosylation.

What condition is associated with MPI p.Pro126= (c.378G>A)?

MPI p.Pro126= (c.378G>A) is associated with MPI-congenital disorder of glycosylation (ClinVar).

How common is MPI p.Pro126= (c.378G>A) in the general population?

MPI p.Pro126= (c.378G>A) is ultra-rare (popmax 0.032%, afr) (gnomAD).

How is MPI-CDG inherited?

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

MPI p.Pro126=

c.378G>A · rs752948071 · VCV317138

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Conditions

MPI-congenital disorder of glycosylation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -3.4
Overall
CADD	9.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.032% African / African-American · 24/74,938 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00242% 39/1,614,104 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.032%	3,122
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
East Asian	0.00668%	14,967
South Asian	0.0022%	45,547
European (non-Finnish)	0.000678%	147,507

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.Pro126=
Coding: c.378G>A
MANE Select: NM_002435
dbSNP: rs752948071
Type: single nucleotide variant
Location: chr15:74892693 (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 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
MPI p.Arg219Gln Pathogenic ★★ ⚠ same condition
MPI p.Arg418His Pathogenic/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-pro126 (accessed [today's date]).

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