Is OPTN p.Pro556Ser (c.1666C>T) pathogenic?

OPTN p.Pro556Ser (c.1666C>T) is classified Uncertain significance in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-01). AlphaMissense: likely pathogenic (0.9794); Absent from gnomAD v4.1; Associated with OPTN-related open angle glaucoma.

What condition is associated with OPTN p.Pro556Ser (c.1666C>T)?

OPTN p.Pro556Ser (c.1666C>T) is associated with OPTN-related open angle glaucoma, amyotrophic lateral sclerosis type 12 (ClinVar).

How common is OPTN p.Pro556Ser (c.1666C>T) in the general population?

OPTN p.Pro556Ser (c.1666C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OPTN p.Pro556Ser (c.1666C>T)?

AlphaMissense predicts likely pathogenic (score 0.9794) — an in-silico prediction, not a clinical call.

OPTN p.Pro556Ser

c.1666C>T · rs2539087117 · VCV2023290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9794 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

OPTN-related open angle glaucoma

Computational evidence

Protein change
AlphaMissense	0.9794	likely pathogenic · top 3% in OPTN
REVEL	0.893	moderately pathogenic-leaning
SaProt	LLR -13.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OPTN
Protein: p.Pro556Ser
Coding: c.1666C>T
MANE Select: NM_001008212
dbSNP: rs2539087117
Type: single nucleotide variant
Location: chr10:13136798 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 556: a turn; the 'interaction with hd' 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 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-pro556ser (accessed [today's date]).

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