Is MPI p.Arg418Cys (c.1252C>T) pathogenic?

MPI p.Arg418Cys (c.1252C>T) is classified Likely pathogenic in MPI (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-14). AlphaMissense: likely pathogenic (0.5918); Ultra-rare (popmax 0.0166%, mid); Associated with MPI-congenital disorder of glycosylation.

What condition is associated with MPI p.Arg418Cys (c.1252C>T)?

MPI p.Arg418Cys (c.1252C>T) is associated with MPI-congenital disorder of glycosylation (ClinVar).

How common is MPI p.Arg418Cys (c.1252C>T) in the general population?

MPI p.Arg418Cys (c.1252C>T) is ultra-rare (popmax 0.0166%, 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.Arg418Cys (c.1252C>T)?

AlphaMissense predicts likely pathogenic (score 0.5918) — an in-silico prediction, not a clinical call.

MPI p.Arg418Cys

c.1252C>T · VCV3358349

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MPI-congenital disorder of glycosylation

Computational evidence

Protein change
AlphaMissense	0.5918	likely pathogenic ✓ concordant with ClinVar
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -12.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,653 bp · p 0.66 · regional, not allelic
Overall
CADD	26.4	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 0.0166% Middle Eastern · 1/6,020 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00217% 35/1,613,972 alleles · ultra-rare exomes 32/1,461,796 · genomes 3/152,176 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,020
Finnishnot grpmax-eligible	0.00469%	21,343
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)	0.00229%	43,705
South Asian	0.0022%	45,542

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.Arg418Cys
Coding: c.1252C>T
MANE Select: NM_002435
Type: single nucleotide variant
Location: chr15:74897710 (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.Arg418His 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
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-arg418cys (accessed [today's date]).

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