Is OPTN p.Arg545Trp (c.1633C>T) pathogenic?

OPTN p.Arg545Trp (c.1633C>T) is classified Conflicting classifications of pathogenicity in OPTN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-03-08). AlphaMissense: likely benign (0.109); Very rare (popmax 0.00356%, nfe); Associated with amyotrophic lateral sclerosis type 12.

What condition is associated with OPTN p.Arg545Trp (c.1633C>T)?

OPTN p.Arg545Trp (c.1633C>T) is associated with amyotrophic lateral sclerosis type 12, OPTN-related open angle glaucoma (ClinVar).

How common is OPTN p.Arg545Trp (c.1633C>T) in the general population?

OPTN p.Arg545Trp (c.1633C>T) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about OPTN p.Arg545Trp (c.1633C>T)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

OPTN p.Arg545Trp

c.1633C>T · rs774245711 · VCV879707

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 12

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.226	benign-leaning
SaProt	LLR -9.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.028	GERP 1.9, phastCons 0.001
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	18.45	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,179,958 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00266% 43/1,613,916 alleles · very rare exomes 41/1,461,756 · genomes 2/152,160 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,094
African / African-American	0.00134%	74,890

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.Arg545Trp
Coding: c.1633C>T
MANE Select: NM_001008212
dbSNP: rs774245711
Type: single nucleotide variant
Location: chr10:13136765 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 545: a UniProt-annotated variant site (in glc1e; uncertain significance); the 'interaction with hd' region

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

Disease context

amyotrophic lateral sclerosis type 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: OPTN-related open angle glaucoma

Similar variants

OPTN p.Arg545Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg545trp (accessed [today's date]).

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