Is OTOG p.Ala460Pro (c.1378G>C) pathogenic?

OTOG p.Ala460Pro (c.1378G>C) is classified Uncertain significance in OTOG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-16). AlphaMissense: likely benign (0.1307); Rare (popmax 0.349%, mid).

How common is OTOG p.Ala460Pro (c.1378G>C) in the general population?

OTOG p.Ala460Pro (c.1378G>C) is rare (popmax 0.349%, mid) (gnomAD).

What do computational predictors say about OTOG p.Ala460Pro (c.1378G>C)?

AlphaMissense predicts likely benign (score 0.1307) — an in-silico prediction, not a clinical call.

OTOG p.Ala460Pro

c.1378G>C · rs764070352 · VCV1308179

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1307 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.349%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1307	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 99 kb · p 0.082 · regional, not allelic
Overall
CADD	21.8	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 is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A472P vs ClinVar A460P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.349% Middle Eastern · 21/6,012 alleles

Filtering AF 0.234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.197%

Overall 0.00232% 36/1,550,564 alleles · rare exomes 30/1,398,356 · genomes 6/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.349%	286
African / African-American	0.0178%	5,619
Admixed American	0.00196%	50,982
Remaining individualsnot grpmax-eligible	0.00166%	60,110

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.Ala460Pro
Coding: c.1378G>C
MANE Select: NM_001292063
dbSNP: rs764070352
Type: single nucleotide variant
Location: chr11:17560744 (GRCh38)
Gene constraint: LOEUF 1.091 · pLI <0.01 (gnomAD)

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

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OTOG p.Arg1222Ter Pathogenic/Likely pathogenic ★★ same type
OTOG p.Arg1903Ter Pathogenic/Likely pathogenic ★★ same type
OTOG p.Arg2175Ter Pathogenic/Likely pathogenic ★★ same type
OTOG p.Arg2473Ter 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-ala460pro (accessed [today's date]).

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