Is MPI p.Ile254= (c.762C>T) pathogenic?

MPI p.Ile254= (c.762C>T) is classified Benign in MPI (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 9.66%, amr) — too common for a highly-penetrant pathogenic allele; Associated with MPI-congenital disorder of glycosylation.

What condition is associated with MPI p.Ile254= (c.762C>T)?

MPI p.Ile254= (c.762C>T) is associated with MPI-congenital disorder of glycosylation (ClinVar).

How is MPI-CDG inherited?

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

MPI p.Ile254=

Q: How common is MPI p.Ile254= (c.762C>T) in the general population?

MPI p.Ile254= (c.762C>T) is common (popmax 9.66%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.762C>T · rs12440159 · VCV94071

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 9.66%, amr) — too common for a highly-penetrant pathogenic allele

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 -0.77, phastCons 1
Overall
CADD	11.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.66% Admixed American · 5,798/60,018 alleles

Filtering AF 9.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.37%

Overall 0.659% 10,637/1,614,204 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	9.66%	10
East Asian	6.44%	16
South Asian	0.856%	117
Remaining individualsnot grpmax-eligible	0.64%	156
African / African-American	0.596%	168
Ashkenazi Jewishnot grpmax-eligible	0.365%	274
Middle Eastern	0.066%	1,516
European (non-Finnish)	0.0176%	5,673
Finnishnot grpmax-eligible	0.00156%	64,046

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.Ile254=
Coding: c.762C>T
MANE Select: NM_002435
dbSNP: rs12440159
Type: single nucleotide variant
Location: chr15:74896243 (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-ile254 (accessed [today's date]).

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