Is MPI p.Arg418His (c.1253G>A) pathogenic?

MPI p.Arg418His (c.1253G>A) is classified Pathogenic/Likely pathogenic in MPI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-19). AlphaMissense: ambiguous (0.4633); Very rare (popmax 0.00267%, afr); Associated with MPI-congenital disorder of glycosylation.

What condition is associated with MPI p.Arg418His (c.1253G>A)?

MPI p.Arg418His (c.1253G>A) is associated with MPI-congenital disorder of glycosylation (ClinVar).

How common is MPI p.Arg418His (c.1253G>A) in the general population?

MPI p.Arg418His (c.1253G>A) is very rare (popmax 0.00267%, 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.Arg418His (c.1253G>A)?

AlphaMissense predicts ambiguous (score 0.4633) — an in-silico prediction, not a clinical call.

MPI p.Arg418His

c.1253G>A · rs863225087 · VCV218095

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4633 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

MPI-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.4633	ambiguous
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -10.95	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,653 bp · p 0.66 · regional, not allelic
Overall
CADD	33.0	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 0.00267% African / African-American · 2/74,884 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000434% 7/1,613,910 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,442
South Asian	0.0011%	91,088
European (non-Finnish)	0.000339%	295,007

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.Arg418His
Coding: c.1253G>A
MANE Select: NM_002435
dbSNP: rs863225087
Type: single nucleotide variant
Location: chr15:74897711 (GRCh38)
Gene constraint: LOEUF 1.04 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.50
Residue 418: a UniProt-annotated variant site (in cdg1b)

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.Arg418Cys 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
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-arg418his (accessed [today's date]).

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