Is MPG p.Pro249Leu (c.746C>T) pathogenic?

MPG p.Pro249Leu (c.746C>T) is classified Uncertain significance in MPG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely benign (0.0785); Ultra-rare (popmax 0.0108%, nfe).

How common is MPG p.Pro249Leu (c.746C>T) in the general population?

MPG p.Pro249Leu (c.746C>T) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

What do computational predictors say about MPG p.Pro249Leu (c.746C>T)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

MPG p.Pro249Leu

c.746C>T · VCV3912632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -1.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.63
Regional constraint	o/e 1.10	unconstrained · MANE · 7,464 bp · p 0.053 · regional, not allelic
Overall
CADD	8.82	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P254L vs ClinVar P249L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0108% European (non-Finnish) · 126/1,165,116 alleles

Filtering AF 0.00923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00866%

Overall 0.0086% 137/1,592,608 alleles · ultra-rare exomes 131/1,440,426 · genomes 6/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0108%	9,247
Remaining individualsnot grpmax-eligible	0.00815%	12,275
African / African-American	0.00538%	18,604
Ashkenazi Jewishnot grpmax-eligible	0.00344%	29,038
Admixed American	0.00171%	58,388

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: MPG
Protein: p.Pro249Leu
Coding: c.746C>T
MANE Select: NM_001015052
Type: single nucleotide variant
Location: chr16:85641 (GRCh38)
Gene constraint: LOEUF 1.468 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.08 · 9 PDB
Residue 254 UniProt numbering: an α-helix

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

Similar variants

MPG p.Val280Ile Uncertain significance ★★ ⚠ same type
MPG p.Ala200Thr Uncertain significance ★ ⚠ same type
MPG p.Ala21Pro Uncertain significance ★ ⚠ same type
MPG p.Ala221Ser Uncertain significance ★ ⚠ same type
MPG p.Ala255Val Uncertain significance ★ ⚠ same type
MPG p.Ala96Glu Uncertain significance ★ ⚠ same type
MPG p.Arg104Gln Uncertain significance ★ ⚠ same type
MPG p.Arg105Gln Uncertain significance ★ ⚠ same type

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/mpg-p-pro249leu (accessed [today's date]).

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