Is OPTN p.Arg548Gln (c.1643G>A) pathogenic?

OPTN p.Arg548Gln (c.1643G>A) is classified Uncertain significance in OPTN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-19). AlphaMissense: likely benign (0.0596); Very rare (popmax 0.00668%, eas); Associated with OPTN-related open angle glaucoma.

What condition is associated with OPTN p.Arg548Gln (c.1643G>A)?

OPTN p.Arg548Gln (c.1643G>A) is associated with OPTN-related open angle glaucoma, amyotrophic lateral sclerosis type 12 (ClinVar).

How common is OPTN p.Arg548Gln (c.1643G>A) in the general population?

OPTN p.Arg548Gln (c.1643G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about OPTN p.Arg548Gln (c.1643G>A)?

AlphaMissense predicts likely benign (score 0.0596) — an in-silico prediction, not a clinical call.

OPTN p.Arg548Gln

c.1643G>A · rs550042475 · VCV1395829

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

OPTN-related open angle glaucoma

Computational evidence

Protein change
AlphaMissense	0.0596	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -5.58	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 0.001	GERP -3.4
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	0.451	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 0.00668% East Asian · 3/44,884 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00204% 33/1,614,076 alleles · very rare exomes 28/1,461,812 · genomes 5/152,264 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,961
Admixed American	0.00333%	30,007
European (non-Finnish)	0.00229%	43,703
African / African-American	0.00133%	75,024

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.Arg548Gln
Coding: c.1643G>A
MANE Select: NM_001008212
dbSNP: rs550042475
Type: single nucleotide variant
Location: chr10:13136775 (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

Also linked: amyotrophic lateral sclerosis type 12

Similar variants

OPTN p.Arg548Trp Uncertain significance ★★ ⚠ same residue
OPTN p.Arg548= Likely benign ★ same residue
OPTN p.Arg548Leu 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

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-arg548gln (accessed [today's date]).

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