Is MPI p.Tyr46= (c.138T>C) pathogenic?

MPI p.Tyr46= (c.138T>C) is classified Likely benign in MPI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-23). Very rare (popmax 0.0011%, sas); Associated with MPI-congenital disorder of glycosylation.

What condition is associated with MPI p.Tyr46= (c.138T>C)?

MPI p.Tyr46= (c.138T>C) is associated with MPI-congenital disorder of glycosylation (ClinVar).

How common is MPI p.Tyr46= (c.138T>C) in the general population?

MPI p.Tyr46= (c.138T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

How is MPI-CDG inherited?

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

MPI p.Tyr46=

c.138T>C · rs2141196187 · VCV1158428

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 -0.31	GERP -2, phastCons 0.45
Overall
CADD	6.651	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,088 alleles

Overall 6.2e-05% 1/1,613,802 alleles · very rare exomes 1/1,461,546 · genomes 0/152,256 · joint denominator

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.Tyr46=
Coding: c.138T>C
MANE Select: NM_002435
dbSNP: rs2141196187
Type: single nucleotide variant
Location: chr15:74890648 (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-tyr46 (accessed [today's date]).

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