Is MPI p.Pro326Arg (c.977C>G) pathogenic?

MPI p.Pro326Arg (c.977C>G) is classified Likely benign in MPI (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-11-10). AlphaMissense: ambiguous (0.3618); Ultra-rare (popmax 0.0507%, afr); Associated with MPI-congenital disorder of glycosylation.

What condition is associated with MPI p.Pro326Arg (c.977C>G)?

MPI p.Pro326Arg (c.977C>G) is associated with MPI-congenital disorder of glycosylation (ClinVar).

How common is MPI p.Pro326Arg (c.977C>G) in the general population?

MPI p.Pro326Arg (c.977C>G) is ultra-rare (popmax 0.0507%, afr) (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.Pro326Arg (c.977C>G)?

AlphaMissense predicts ambiguous (score 0.3618) — an in-silico prediction, not a clinical call.

MPI p.Pro326Arg

c.977C>G · rs199956743 · VCV989849

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3618 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0507%, afr)

Conditions

MPI-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.3618	ambiguous
REVEL	0.388	indeterminate
SaProt	LLR -14.19	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 7,653 bp · p 0.66 · regional, not allelic
Overall
CADD	22.9	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 0.0507% African / African-American · 38/74,934 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0335%

Overall 0.00242% 39/1,614,108 alleles · ultra-rare exomes 21/1,461,890 · genomes 18/152,218 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0507%	1,972
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Pro326Arg
Coding: c.977C>G
MANE Select: NM_002435
dbSNP: rs199956743
Type: single nucleotide variant
Location: chr15:74897143 (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.Pro326Ser Uncertain significance ★★ ⚠ 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
MPI p.Arg219Gln 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-pro326arg (accessed [today's date]).

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