Is OPTN p.Val147= (c.441G>A) pathogenic?

OPTN p.Val147= (c.441G>A) is classified Conflicting classifications of pathogenicity in OPTN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-26). Very rare (popmax 0.0011%, sas); Associated with Glaucoma 1, open angle, E.

What condition is associated with OPTN p.Val147= (c.441G>A)?

OPTN p.Val147= (c.441G>A) is associated with Glaucoma 1, open angle, E, amyotrophic lateral sclerosis type 12, OPTN-related open angle glaucoma (ClinVar).

How common is OPTN p.Val147= (c.441G>A) in the general population?

OPTN p.Val147= (c.441G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

OPTN p.Val147=

c.441G>A · rs886046819 · VCV299212

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Glaucoma 1, open angle, E

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 3.3	GERP 0.5, phastCons 1
Overall
CADD	5.358	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,078 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,118 alleles · very rare exomes 4/1,461,886 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,078
European (non-Finnish)	0.000254%	393,340

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.Val147=
Coding: c.441G>A
MANE Select: NM_001008212
dbSNP: rs886046819
Type: single nucleotide variant
Location: chr10:13112524 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 147: the 'interaction with rab8' region; an α-helix

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

Disease context

Glaucoma 1, open angle, E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 12 OPTN-related open angle glaucoma

Similar variants

OPTN p.Val147Glu Uncertain significance ★ ⚠ same residue
OPTN p.Val147Ala Uncertain significance ★ ⚠ same residue
OPTN p.Val147Leu 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-val147 (accessed [today's date]).

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