Is MPG p.Arg256Trp (c.766C>T) pathogenic?

MPG p.Arg256Trp (c.766C>T) is classified Uncertain significance in MPG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely pathogenic (0.6989); Very rare (popmax 0.0045%, sas).

How common is MPG p.Arg256Trp (c.766C>T) in the general population?

MPG p.Arg256Trp (c.766C>T) is very rare (popmax 0.0045%, sas) (gnomAD).

What do computational predictors say about MPG p.Arg256Trp (c.766C>T)?

AlphaMissense predicts likely pathogenic (score 0.6989) — an in-silico prediction, not a clinical call.

MPG p.Arg256Trp

c.766C>T · rs150131864 · VCV2400860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0045%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6989	likely pathogenic
REVEL	0.535	indeterminate
SaProt	LLR -12.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 7,464 bp · p 0.053 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 R261W vs ClinVar R256W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0045% South Asian · 4/88,800 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000909%

Overall 0.00101% 16/1,584,164 alleles · very rare exomes 13/1,431,970 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00656%	15,236
South Asiangrpmax	0.0045%	22,200
Admixed American	0.00349%	28,661
East Asian	0.00226%	44,284
European (non-Finnish)	0.000431%	232,220

Remaining individuals 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: MPG
Protein: p.Arg256Trp
Coding: c.766C>T
MANE Select: NM_001015052
dbSNP: rs150131864
Type: single nucleotide variant
Location: chr16:85661 (GRCh38)
Gene constraint: LOEUF 1.468 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.08 · 9 PDB

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

Similar variants

MPG p.Arg256= Likely benign ★ same residue
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

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-arg256trp (accessed [today's date]).

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