Is OTUD7B p.Pro751Arg (c.2252C>G) pathogenic?

OTUD7B p.Pro751Arg (c.2252C>G) is classified Uncertain significance in OTUD7B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.0759); Very rare (popmax 0.00534%, afr).

How common is OTUD7B p.Pro751Arg (c.2252C>G) in the general population?

OTUD7B p.Pro751Arg (c.2252C>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about OTUD7B p.Pro751Arg (c.2252C>G)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

OTUD7B p.Pro751Arg

c.2252C>G · VCV4563627

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.1	GERP -2.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 989 bp · p 0.74 · regional, not allelic
Overall
CADD	15.95	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 0.00534% African / African-American · 4/74,916 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,613,922 alleles · very rare exomes 0/1,461,748 · genomes 4/152,174 · 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: OTUD7B
Protein: p.Pro751Arg
Coding: c.2252C>G
MANE Select: NM_020205
Type: single nucleotide variant
Location: chr1:149944137 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.87 (gnomAD)
Structure: AlphaFold pLDDT 67.63 · 3 PDB
Residue 751: the 'disordered' region

Full OTUD7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

OTUD7B p.Asp407= Benign ★★ same type
OTUD7B p.Gly59= Benign ★★ same type
OTUD7B p.Pro701= Benign ★★ same type
OTUD7B p.Ala278Thr Uncertain significance ★ ⚠ same type
OTUD7B p.Ala303Thr Uncertain significance ★ ⚠ same type
OTUD7B p.Ala342Val Uncertain significance ★ ⚠ same type
OTUD7B p.Ala361Ser Uncertain significance ★ ⚠ same type
OTUD7B p.Ala452Thr 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/otud7b-p-pro751arg (accessed [today's date]).

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