Is OTOA p.Pro769Ser (c.2305C>T) pathogenic?

OTOA p.Pro769Ser (c.2305C>T) is classified Uncertain significance in OTOA (ClinVar, Single submitter, 1 submitter; last evaluated 2018-02-28). AlphaMissense: likely benign (0.2462); Very rare (popmax 0.00424%, nfe).

How common is OTOA p.Pro769Ser (c.2305C>T) in the general population?

OTOA p.Pro769Ser (c.2305C>T) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about OTOA p.Pro769Ser (c.2305C>T)?

AlphaMissense predicts likely benign (score 0.2462) — an in-silico prediction, not a clinical call.

OTOA p.Pro769Ser

c.2305C>T · rs769182891 · VCV666891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2462 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2462	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -7.86	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 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 21 kb · p 0.73 · regional, not allelic
Overall
CADD	24.1	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 P783S vs ClinVar P769S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00424% European (non-Finnish) · 50/1,178,590 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00316% 51/1,612,332 alleles · very rare exomes 50/1,460,274 · genomes 1/152,058 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00424%	23,572
African / African-American	0.00134%	74,844

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: OTOA
Protein: p.Pro769Ser
Coding: c.2305C>T
MANE Select: NM_144672
dbSNP: rs769182891
Type: single nucleotide variant
Location: chr16:21736264 (GRCh38)
Gene constraint: LOEUF 0.822 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.12

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

Similar variants

OTOA c.1320+2T>C Pathogenic ★★ same type
OTOA c.1880+1G>A Pathogenic/Likely pathogenic ★★ same type
OTOA c.399+2T>C Pathogenic/Likely pathogenic ★★ same type
OTOA c.635+2T>A Pathogenic/Likely pathogenic ★★ same type
OTOA c.92-1G>T Pathogenic/Likely pathogenic ★★ same type
OTOA p.Arg146Ter Pathogenic/Likely pathogenic ★★ same type
OTOA p.Arg148Ter Pathogenic ★★ same type
OTOA p.Lys667Glu Likely pathogenic ★★ 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/otoa-p-pro769ser (accessed [today's date]).

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