Is OMD p.Pro257Leu (c.770C>T) pathogenic?

OMD p.Pro257Leu (c.770C>T) is classified Uncertain significance in OMD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.1591); Rare (popmax 0.389%, nfe).

How common is OMD p.Pro257Leu (c.770C>T) in the general population?

OMD p.Pro257Leu (c.770C>T) is rare (popmax 0.389%, nfe) (gnomAD).

What do computational predictors say about OMD p.Pro257Leu (c.770C>T)?

AlphaMissense predicts likely benign (score 0.1591) — an in-silico prediction, not a clinical call.

OMD p.Pro257Leu

c.770C>T · VCV4125576

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1591 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.389%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1591	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 2,403 bp · p 0.054 · regional, not allelic
Overall
CADD	23.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.389% European (non-Finnish) · 4,593/1,179,778 alleles

Filtering AF 0.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.376%

Overall 0.327% 5,278/1,613,714 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.524%	191
European (non-Finnish)grpmax	0.389%	257
Remaining individualsnot grpmax-eligible	0.318%	314
Finnishnot grpmax-eligible	0.222%	451
Middle Eastern	0.165%	605
Admixed American	0.0733%	1,364
South Asian	0.0725%	1,380
African / African-American	0.0667%	1,500
East Asian	0.0424%	2,359

Ashkenazi Jewish 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: OMD
Protein: p.Pro257Leu
Coding: c.770C>T
MANE Select: NM_001012267 · reported on NM_005014
Type: single nucleotide variant
Location: chr9:92416789 (GRCh38)

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

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/omd-p-pro257leu (accessed [today's date]).

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