Is OPTN p.Pro5Arg (c.14C>G) pathogenic?

OPTN p.Pro5Arg (c.14C>G) is classified Uncertain significance in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-02). AlphaMissense: likely benign (0.1326); Very rare (popmax 0.000169%, nfe); Associated with OPTN-related open angle glaucoma.

What condition is associated with OPTN p.Pro5Arg (c.14C>G)?

OPTN p.Pro5Arg (c.14C>G) is associated with OPTN-related open angle glaucoma, amyotrophic lateral sclerosis type 12 (ClinVar).

How common is OPTN p.Pro5Arg (c.14C>G) in the general population?

OPTN p.Pro5Arg (c.14C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about OPTN p.Pro5Arg (c.14C>G)?

AlphaMissense predicts likely benign (score 0.1326) — an in-silico prediction, not a clinical call.

OPTN p.Pro5Arg

c.14C>G · rs1564354765 · VCV565324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1326 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

OPTN-related open angle glaucoma

Computational evidence

Protein change
AlphaMissense	0.1326	likely benign
REVEL	0.44	indeterminate
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.25	acceptor loss, 7 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 2.7	GERP 1.7, phastCons 0.079
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,016 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,066 alleles · very rare exomes 2/1,461,802 · genomes 0/152,264 · joint denominator

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.Pro5Arg
Coding: c.14C>G
MANE Select: NM_001008212
dbSNP: rs1564354765
Type: single nucleotide variant
Location: chr10:13109136 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 5: the 'disordered' 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-pro5arg (accessed [today's date]).

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