Is OTOA p.Ala477Pro (c.1429G>C) pathogenic?

OTOA p.Ala477Pro (c.1429G>C) is classified Uncertain significance in OTOA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-04-06). AlphaMissense: likely benign (0.0867); Ultra-rare (popmax 0.0123%, nfe); Associated with Inborn genetic diseases.

What condition is associated with OTOA p.Ala477Pro (c.1429G>C)?

OTOA p.Ala477Pro (c.1429G>C) is associated with Inborn genetic diseases (ClinVar).

How common is OTOA p.Ala477Pro (c.1429G>C) in the general population?

OTOA p.Ala477Pro (c.1429G>C) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

What do computational predictors say about OTOA p.Ala477Pro (c.1429G>C)?

AlphaMissense predicts likely benign (score 0.0867) — an in-silico prediction, not a clinical call.

OTOA p.Ala477Pro

c.1429G>C · rs55890908 · VCV2683349

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0867	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -4.12	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 -3.4	GERP -3
Regional constraint	o/e 0.92	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	0.034	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 A491P vs ClinVar A477P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% European (non-Finnish) · 145/1,180,046 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.00973% 157/1,614,118 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0123%	8,138
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed American	0.005%	20,004
African / African-American	0.00267%	37,468

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.Ala477Pro
Coding: c.1429G>C
MANE Select: NM_144672
dbSNP: rs55890908
Type: single nucleotide variant
Location: chr16:21715093 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OTOA p.Ala477= Likely benign ★ same residue
OTOA p.Ala364Thr Uncertain significance ★★ ⚠ same condition
OTOA p.Ala40Val Uncertain significance ★★ ⚠ same condition
OTOA p.Arg1027Trp Uncertain significance ★★ ⚠ same condition
OTOA p.Arg202Pro Uncertain significance ★★ ⚠ same condition
OTOA p.Arg29Lys Uncertain significance ★★ ⚠ same condition
OTOA p.Arg475Lys Uncertain significance ★★ ⚠ same condition
OTOA p.Arg797Trp Uncertain significance ★★ ⚠ same condition

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-ala477pro (accessed [today's date]).

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