Is OPTN p.Glu194= (c.582A>G) pathogenic?

OPTN p.Glu194= (c.582A>G) is classified Likely benign in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-28). Very rare (popmax 0.00333%, amr); Associated with amyotrophic lateral sclerosis type 12.

What condition is associated with OPTN p.Glu194= (c.582A>G)?

OPTN p.Glu194= (c.582A>G) is associated with amyotrophic lateral sclerosis type 12, OPTN-related open angle glaucoma (ClinVar).

How common is OPTN p.Glu194= (c.582A>G) in the general population?

OPTN p.Glu194= (c.582A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

OPTN p.Glu194=

c.582A>G · rs776613114 · VCV2931742

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

amyotrophic lateral sclerosis type 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.019	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 0.59, phastCons 0.99
Overall
CADD	9.166	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,998 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00192% 31/1,613,448 alleles · very rare exomes 30/1,461,248 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,999
European (non-Finnish)	0.00237%	42,125
African / African-American	0.00133%	74,908

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.Glu194=
Coding: c.582A>G
MANE Select: NM_001008212
dbSNP: rs776613114
Type: single nucleotide variant
Location: chr10:13116296 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 194: the 'interaction with rab8' region; the 'disordered' region

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

Disease context

amyotrophic lateral sclerosis type 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: OPTN-related open angle glaucoma

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-glu194 (accessed [today's date]).

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