Is OTOG p.Pro780= (c.2340G>A) pathogenic?

OTOG p.Pro780= (c.2340G>A) is classified Benign in OTOG (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 40.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 18B.

What condition is associated with OTOG p.Pro780= (c.2340G>A)?

OTOG p.Pro780= (c.2340G>A) is associated with autosomal recessive nonsyndromic hearing loss 18B (ClinVar).

OTOG p.Pro780=

Q: How common is OTOG p.Pro780= (c.2340G>A) in the general population?

OTOG p.Pro780= (c.2340G>A) is common (popmax 40.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2340G>A · rs4757548 · VCV226868

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 40.4%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

autosomal recessive nonsyndromic hearing loss 18B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -4.5
Overall
CADD	2.274	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 40.4% European (non-Finnish) · 463,521/1,146,808 alleles

Filtering AF 40.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 40.3%

Overall 38.5% 596,630/1,550,218 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	44.8%	2
European (non-Finnish)grpmax	40.4%	2
Ashkenazi Jewishnot grpmax-eligible	38.4%	3
Finnishnot grpmax-eligible	37.8%	3
Remaining individualsnot grpmax-eligible	37.7%	3
African / African-American	37.2%	3
Middle Eastern	35.3%	3
South Asian	31.6%	3
East Asian	23.3%	4
Admixed American	22.5%	4

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro780=
Coding: c.2340G>A
MANE Select: NM_001292063
dbSNP: rs4757548
Type: single nucleotide variant
Location: chr11:17574766 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 (gnomAD)
Residue 780: the til 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-pro780 (accessed [today's date]).

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