Is OTOA p.Ser78Pro (c.232T>C) pathogenic?

OTOA p.Ser78Pro (c.232T>C) is classified Uncertain significance in OTOA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-22). AlphaMissense: ambiguous (0.5044); Very rare (popmax 0.000169%, nfe).

How common is OTOA p.Ser78Pro (c.232T>C) in the general population?

OTOA p.Ser78Pro (c.232T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about OTOA p.Ser78Pro (c.232T>C)?

AlphaMissense predicts ambiguous (score 0.5044) — an in-silico prediction, not a clinical call.

OTOA p.Ser78Pro

c.232T>C · rs995856279 · VCV1505417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5044 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5044	ambiguous
REVEL	0.187	benign-leaning
SaProt	LLR -13.66	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP -3.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,988 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,028 alleles · very rare exomes 2/1,461,870 · genomes 0/152,158 · 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: OTOA
Protein: p.Ser78Pro
Coding: c.232T>C
MANE Select: NM_144672
dbSNP: rs995856279
Type: single nucleotide variant
Location: chr16:21681790 (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-ser78pro (accessed [today's date]).

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