Is OPTN p.Ser321= (c.963C>T) pathogenic?

OPTN p.Ser321= (c.963C>T) is classified Benign/Likely benign in OPTN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-19). Low-frequency (popmax 1.66%, afr); Associated with Glaucoma 1, open angle, E.

What condition is associated with OPTN p.Ser321= (c.963C>T)?

OPTN p.Ser321= (c.963C>T) is associated with Glaucoma 1, open angle, E, amyotrophic lateral sclerosis type 12, OPTN-related open angle glaucoma (ClinVar).

How common is OPTN p.Ser321= (c.963C>T) in the general population?

OPTN p.Ser321= (c.963C>T) is low-frequency (popmax 1.66%, afr) (gnomAD).

OPTN p.Ser321=

c.963C>T · rs150381274 · VCV299218

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.66%, afr)

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 -0.15	GERP -3.5, phastCons 0.75
Overall
CADD	10.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.66% African / African-American · 1,247/74,996 alleles

Filtering AF 1.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.56%

Overall 0.0923% 1,488/1,612,530 alleles · low-frequency exomes 750/1,460,296 · genomes 738/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.66%	60
Remaining individualsnot grpmax-eligible	0.155%	644
Admixed American	0.147%	681
Middle Eastern	0.0826%	1,211
East Asian	0.0111%	8,971
South Asian	0.0099%	10,102
European (non-Finnish)	0.00314%	31,862

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.Ser321=
Coding: c.963C>T
MANE Select: NM_001008212
dbSNP: rs150381274
Type: single nucleotide variant
Location: chr10:13124075 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB

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.Ser321Cys 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-ser321 (accessed [today's date]).

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