Is OTOG p.Ser680Pro (c.2038T>C) pathogenic?

OTOG p.Ser680Pro (c.2038T>C) is classified Benign in OTOG (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0499); Common (popmax 63%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 18B.

What condition is associated with OTOG p.Ser680Pro (c.2038T>C)?

OTOG p.Ser680Pro (c.2038T>C) is associated with autosomal recessive nonsyndromic hearing loss 18B (ClinVar).

What do computational predictors say about OTOG p.Ser680Pro (c.2038T>C)?

AlphaMissense predicts likely benign (score 0.0499) — an in-silico prediction, not a clinical call.

OTOG p.Ser680Pro

Q: How common is OTOG p.Ser680Pro (c.2038T>C) in the general population?

OTOG p.Ser680Pro (c.2038T>C) is common (popmax 63%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2038T>C · rs7106548 · VCV226866

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0499 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 63%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

autosomal recessive nonsyndromic hearing loss 18B

Computational evidence

Protein change
AlphaMissense	0.0499	likely benign
REVEL	0.017	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.36	GERP -5.2
Regional constraint	o/e 1.03	unconstrained · MANE · 99 kb · p 0.082 · regional, not allelic
Overall
CADD	8.379	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S692P vs ClinVar S680P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 63% African / African-American · 45,977/72,950 alleles

Filtering AF 62.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 62.3%

Overall 43.6% 676,004/1,549,820 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	63%	2
Amishnot grpmax-eligible	49.8%	2
Ashkenazi Jewishnot grpmax-eligible	44.3%	2
European (non-Finnish)	44.3%	2
Remaining individualsnot grpmax-eligible	43%	2
Finnishnot grpmax-eligible	40.5%	2
Middle Eastern	39.4%	3
South Asian	38.4%	3
Admixed American	28.4%	4
East Asian	26%	4

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: OTOG
Protein: p.Ser680Pro
Coding: c.2038T>C
MANE Select: NM_001292063
dbSNP: rs7106548
Type: single nucleotide variant
Location: chr11:17572162 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 (gnomAD)
Residue 680: a disulfide bond; the vwfd 2 domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 18B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OTOG p.Arg1063Ter Pathogenic/Likely pathogenic ★★ same condition
OTOG p.Arg1153Ter Pathogenic/Likely pathogenic ★★ same condition
OTOG p.Arg1222Ter Pathogenic/Likely pathogenic ★★ same condition
OTOG p.Arg2175Ter Pathogenic/Likely pathogenic ★★ same condition
OTOG p.Arg2473Ter Pathogenic/Likely pathogenic ★★ same condition
OTOG p.Gln127Ter Pathogenic/Likely pathogenic ★★ same condition
OTOG p.Gln556Ter Pathogenic/Likely pathogenic ★★ same condition
OTOG p.Gln822Ter Pathogenic/Likely pathogenic ★★ 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/otog-p-ser680pro (accessed [today's date]).

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