OPTN p.Ala136=
c.408G>A · rs144561412 · VCV1976333
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0165%, mid)
Conditions
2
amyotrophic lateral sclerosis type 12
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -0.36 | GERP -4.6 |
| Overall | ||
| CADD | 2.446 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0165%
Middle Eastern · 1/6,062 alleles
Filtering AF
0.00435%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00276%
Overall
0.00384%
62/1,613,946 alleles · ultra-rare
exomes 54/1,461,878 · genomes 8/152,068 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0165% | 6,062 |
| East Asian | 0.0111% | 8,970 |
| European (non-Finnish) | 0.00398% | 25,106 |
| Admixed American | 0.00333% | 30,001 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,252 |
| African / African-American | 0.00267% | 37,470 |
| South Asian | 0.0022% | 45,535 |
| Finnishnot grpmax-eligible | 0.00156% | 64,008 |
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.Ala136=
- Coding
- c.408G>A
- MANE Select
- NM_001008212
- dbSNP
- rs144561412
- Type
- single nucleotide variant
- Location
- chr10:13112491 (GRCh38)
- Gene constraint
- LOEUF 0.877 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 77.90 · 14 PDB
- Residue 136
- the 'interaction with rab8' region; the 'disordered' region; an α-helix
Similar variants
- OPTN p.Ala136Val Uncertain significance ★★ ⚠ same residue
- 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
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-ala136 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown