Is OTOG p.Arg980Pro (c.2939G>C) pathogenic?

OTOG p.Arg980Pro (c.2939G>C) is classified Uncertain significance in OTOG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-05). AlphaMissense: likely pathogenic (0.8315); Very rare (popmax 0.00209%, nfe).

How common is OTOG p.Arg980Pro (c.2939G>C) in the general population?

OTOG p.Arg980Pro (c.2939G>C) is very rare (popmax 0.00209%, nfe) (gnomAD).

What do computational predictors say about OTOG p.Arg980Pro (c.2939G>C)?

AlphaMissense predicts likely pathogenic (score 0.8315) — an in-silico prediction, not a clinical call.

OTOG p.Arg980Pro

c.2939G>C · rs876657938 · VCV229087

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00209%, nfe)

Computational evidence

Protein change
AlphaMissense	0.8315	likely pathogenic
REVEL	0.463	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 99 kb · p 0.082 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R992P vs ClinVar R980P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00209% European (non-Finnish) · 24/1,147,028 alleles

Filtering AF 0.00142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00119%

Overall 0.00168% 26/1,550,562 alleles · very rare exomes 21/1,398,356 · genomes 5/152,206 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00333%	30,048
European (non-Finnish)grpmax	0.00209%	47,793

Remaining individuals 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.Arg980Pro
Coding: c.2939G>C
MANE Select: NM_001292063
dbSNP: rs876657938
Type: single nucleotide variant
Location: chr11:17591521 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 (gnomAD)

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

Similar variants

OTOG p.Arg980= Likely benign ★ same residue
OTOG c.6934-2A>G Likely pathogenic ★★ same type
OTOG c.996+1G>T Pathogenic ★★ same type
OTOG p.Arg1063Ter Pathogenic/Likely pathogenic ★★ same type
OTOG p.Arg1153Ter Pathogenic/Likely pathogenic ★★ same type
OTOG p.Arg1222Ter Pathogenic/Likely pathogenic ★★ same type
OTOG p.Arg1903Ter Pathogenic/Likely pathogenic ★★ same type
OTOG p.Arg2175Ter Pathogenic/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/otog-p-arg980pro (accessed [today's date]).

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