OPTN p.Pro199=
c.597T>C · rs373699827 · VCV719734
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0936%, eas)
Conditions
2
amyotrophic lateral sclerosis type 12
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.031 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP -0.95 | GERP -5.8 |
| Overall | ||
| CADD | 6.821 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0936%
East Asian · 42/44,870 alleles
Filtering AF
0.0712%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0632%
Overall
0.00434%
70/1,613,782 alleles · ultra-rare
exomes 61/1,461,482 · genomes 9/152,300 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.0936% | 1,068 |
| Remaining individualsnot grpmax-eligible | 0.0224% | 4,463 |
| South Asian | 0.0121% | 8,280 |
| European (non-Finnish) | 0.000254% | 393,244 |
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
- OPTN
- Protein
- p.Pro199=
- Coding
- c.597T>C
- MANE Select
- NM_001008212
- dbSNP
- rs373699827
- Type
- single nucleotide variant
- Location
- chr10:13116311 (GRCh38)
- Gene constraint
- LOEUF 0.877 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 77.90 · 14 PDB
- Residue 199
- the 'interaction with rab8' region; the 'disordered' region
Similar variants
- OPTN c.1149-2A>G Likely pathogenic ★★ same condition
- OPTN c.626+1G>A Likely pathogenic ★★ same condition
- OPTN c.780-2A>C Likely pathogenic ★★ same condition
- OPTN p.Gln165Ter Pathogenic/Likely pathogenic ★★ same condition
- OPTN p.Gln335Ter Pathogenic ★★ same condition
- OPTN p.Gln79Ter Pathogenic/Likely pathogenic ★★ same condition
- OPTN p.Glu135Ter Pathogenic ★★ same condition
- OPTN p.Glu399Ter 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/optn-p-pro199 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown