Is OTOG p.Pro2002Leu (c.6005C>T) pathogenic?

OTOG p.Pro2002Leu (c.6005C>T) is classified Uncertain significance in OTOG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0671); Rare (popmax 0.203%, eas).

How common is OTOG p.Pro2002Leu (c.6005C>T) in the general population?

OTOG p.Pro2002Leu (c.6005C>T) is rare (popmax 0.203%, eas) (gnomAD).

What do computational predictors say about OTOG p.Pro2002Leu (c.6005C>T)?

AlphaMissense predicts likely benign (score 0.0671) — an in-silico prediction, not a clinical call.

OTOG p.Pro2002Leu

c.6005C>T · rs536679514 · VCV1802127

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0671 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.203%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0671	likely benign
REVEL	0.011	strongly 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 -0.91	GERP -3.9
Regional constraint	o/e 1.03	unconstrained · MANE · 99 kb · p 0.082 · regional, not allelic
Overall
CADD	2.101	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 P2014L vs ClinVar P2002L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.203% East Asian · 83/40,902 alleles

Filtering AF 0.168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.155%

Overall 0.00942% 146/1,550,588 alleles · rare exomes 131/1,398,264 · genomes 15/152,324 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.203%	493
Ashkenazi Jewishnot grpmax-eligible	0.0175%	5,730
Remaining individualsnot grpmax-eligible	0.00666%	15,026
European (non-Finnish)	0.00445%	22,490
African / African-American	0.00273%	36,592
South Asian	0.00119%	84,052

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.Pro2002Leu
Coding: c.6005C>T
MANE Select: NM_001292063
dbSNP: rs536679514
Type: single nucleotide variant
Location: chr11:17611305 (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.Pro2002= 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-pro2002leu (accessed [today's date]).

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