Is OTOA p.Pro407Ser (c.1219C>T) pathogenic?

OTOA p.Pro407Ser (c.1219C>T) is classified Uncertain significance in OTOA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-17). AlphaMissense: likely benign (0.1107); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with OTOA p.Pro407Ser (c.1219C>T)?

OTOA p.Pro407Ser (c.1219C>T) is associated with Inborn genetic diseases (ClinVar).

How common is OTOA p.Pro407Ser (c.1219C>T) in the general population?

OTOA p.Pro407Ser (c.1219C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about OTOA p.Pro407Ser (c.1219C>T)?

AlphaMissense predicts likely benign (score 0.1107) — an in-silico prediction, not a clinical call.

OTOA p.Pro407Ser

c.1219C>T · rs772723589 · VCV2486812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1107 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1107	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -7.50	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 1.7	GERP 1.6, phastCons 0.92
Regional constraint	o/e 0.92	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	18.35	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 P421S vs ClinVar P407S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,880 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00347% 56/1,614,096 alleles · very rare exomes 56/1,461,836 · genomes 0/152,260 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,220
European (non-Finnish)	0.00424%	23,600
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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.Pro407Ser
Coding: c.1219C>T
MANE Select: NM_144672
dbSNP: rs772723589
Type: single nucleotide variant
Location: chr16:21710002 (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.Pro407= Likely benign ★ same residue
OTOA p.Ala364Thr Uncertain significance ★★ ⚠ same condition
OTOA p.Ala40Val Uncertain significance ★★ ⚠ same condition
OTOA p.Ala477Pro 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

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-pro407ser (accessed [today's date]).

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