Is MPI p.Arg219Gln (c.656G>A) pathogenic?

MPI p.Arg219Gln (c.656G>A) is classified Pathogenic in MPI (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.2355); Ultra-rare (popmax 0.0311%, nfe); Associated with MPI-related disorder.

What condition is associated with MPI p.Arg219Gln (c.656G>A)?

MPI p.Arg219Gln (c.656G>A) is associated with MPI-related disorder, MPI-congenital disorder of glycosylation (ClinVar).

How common is MPI p.Arg219Gln (c.656G>A) in the general population?

MPI p.Arg219Gln (c.656G>A) is ultra-rare (popmax 0.0311%, nfe) (gnomAD).

What do computational predictors say about MPI p.Arg219Gln (c.656G>A)?

AlphaMissense predicts likely benign (score 0.2355) — an in-silico prediction, not a clinical call.

MPI p.Arg219Gln

c.656G>A · rs104894489 · VCV14345

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.2355 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0311%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MPI-related disorder

Computational evidence

Protein change
AlphaMissense	0.2355	likely benign ⚠ discordant with ClinVar
REVEL	0.885	moderately pathogenic-leaning
SaProt	LLR -11.41	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.3, 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 0.0311% European (non-Finnish) · 367/1,180,038 alleles

Filtering AF 0.0285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0274%

Overall 0.0268% 433/1,614,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.05%	2,002
Remaining individualsnot grpmax-eligible	0.0384%	2,604
European (non-Finnish)grpmax	0.0311%	3,215
African / African-American	0.0133%	7,492

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg219Gln
Coding: c.656G>A
MANE Select: NM_002435
dbSNP: rs104894489
Type: single nucleotide variant
Location: chr15:74893306 (GRCh38)
Gene constraint: LOEUF 1.04 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.50
Residue 219: a UniProt-annotated variant site (in cdg1b)

Full MPI gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MPI-related disorder

Also linked: MPI-congenital disorder of glycosylation

Similar variants

MPI p.Arg219Trp Likely pathogenic ★ same residue
MPI p.Arg219= Likely benign ★ 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-arg219gln (accessed [today's date]).

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