Is OPTN p.Val418= (c.1254G>A) pathogenic?

OPTN p.Val418= (c.1254G>A) is classified Likely benign in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-19). Very rare (popmax 0.005%, amr); Associated with OPTN-related open angle glaucoma.

What condition is associated with OPTN p.Val418= (c.1254G>A)?

OPTN p.Val418= (c.1254G>A) is associated with OPTN-related open angle glaucoma, amyotrophic lateral sclerosis type 12 (ClinVar).

How common is OPTN p.Val418= (c.1254G>A) in the general population?

OPTN p.Val418= (c.1254G>A) is very rare (popmax 0.005%, amr) (gnomAD).

OPTN p.Val418=

c.1254G>A · VCV3762212

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

OPTN-related open angle glaucoma

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 0.17	GERP -1.3, phastCons 0.86
Overall
CADD	7.723	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,996 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000496% 8/1,614,000 alleles · very rare exomes 7/1,461,834 · genomes 1/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,912
South Asian	0.0011%	91,090
European (non-Finnish)	0.000169%	589,995

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.Val418=
Coding: c.1254G>A
MANE Select: NM_001008212
Type: single nucleotide variant
Location: chr10:13127756 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 418: the 'interaction with hd' region; the 'interaction with myo6' region

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

Disease context

Also linked: amyotrophic lateral sclerosis type 12

Similar variants

OPTN p.Val418Ala Uncertain significance ★ ⚠ same residue
OPTN p.Val418Leu Uncertain significance ★ same residue
OPTN p.Val418Gly 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

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-val418 (accessed [today's date]).

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