Is OPTN p.Arg548Trp (c.1642C>T) pathogenic?

OPTN p.Arg548Trp (c.1642C>T) is classified Uncertain significance in OPTN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-02). AlphaMissense: likely benign (0.123); Very rare (popmax 0.00667%, amr); Associated with Inborn genetic diseases.

What condition is associated with OPTN p.Arg548Trp (c.1642C>T)?

OPTN p.Arg548Trp (c.1642C>T) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 12, OPTN-related open angle glaucoma (ClinVar).

How common is OPTN p.Arg548Trp (c.1642C>T) in the general population?

OPTN p.Arg548Trp (c.1642C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about OPTN p.Arg548Trp (c.1642C>T)?

AlphaMissense predicts likely benign (score 0.123) — an in-silico prediction, not a clinical call.

OPTN p.Arg548Trp

c.1642C>T · rs767360238 · VCV1409198

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.123 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.123	likely benign
REVEL	0.159	moderately benign-leaning
SaProt	LLR -9.33	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 3.6	GERP 0.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	18.02	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 0.00667% Admixed American · 4/59,994 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000991% 16/1,613,970 alleles · very rare exomes 15/1,461,792 · genomes 1/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0048%	20,825
African / African-American	0.004%	24,971
South Asian	0.0011%	91,078
European (non-Finnish)	0.000424%	235,997

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.Arg548Trp
Coding: c.1642C>T
MANE Select: NM_001008212
dbSNP: rs767360238
Type: single nucleotide variant
Location: chr10:13136774 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 548: the 'interaction with hd' region

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

Disease context

Inborn genetic diseases — 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.Arg548Gln Uncertain significance ★★ ⚠ same residue
OPTN p.Arg548Leu Uncertain significance ★★ ⚠ same residue
OPTN p.Arg548= Likely benign ★ 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-arg548trp (accessed [today's date]).

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