Is OPTN p.Ile577Thr (c.1730T>C) pathogenic?

OPTN p.Ile577Thr (c.1730T>C) is classified Uncertain significance in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-23). AlphaMissense: likely pathogenic (0.8663); Very rare (popmax 0.00407%, nfe); Associated with Inborn genetic diseases.

What condition is associated with OPTN p.Ile577Thr (c.1730T>C)?

OPTN p.Ile577Thr (c.1730T>C) is associated with Inborn genetic diseases (ClinVar).

How common is OPTN p.Ile577Thr (c.1730T>C) in the general population?

OPTN p.Ile577Thr (c.1730T>C) is very rare (popmax 0.00407%, nfe) (gnomAD).

What do computational predictors say about OPTN p.Ile577Thr (c.1730T>C)?

AlphaMissense predicts likely pathogenic (score 0.8663) — an in-silico prediction, not a clinical call.

OPTN p.Ile577Thr

c.1730T>C · rs552807448 · VCV1778975

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8663	likely pathogenic · top 10% in OPTN
REVEL	0.584	indeterminate
SaProt	LLR -6.19	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	25.2	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 0.00407% European (non-Finnish) · 48/1,180,038 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.0031% 50/1,614,244 alleles · very rare exomes 46/1,461,882 · genomes 4/152,362 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00407%	24,584
African / African-American	0.00266%	37,535

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.Ile577Thr
Coding: c.1730T>C
MANE Select: NM_001008212
dbSNP: rs552807448
Type: single nucleotide variant
Location: chr10:13136862 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 577: 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

Similar variants

OPTN p.Gln335Ter Pathogenic ★★ same condition
OPTN c.1402-3C>G Uncertain significance ★★ same condition
OPTN c.882+5G>C Uncertain significance ★★ same condition
OPTN p.Ala466Ser Uncertain significance ★★ ⚠ same condition
OPTN p.Arg271Pro Uncertain significance ★★ ⚠ same condition
OPTN p.Arg548Leu Uncertain significance ★★ ⚠ same condition
OPTN p.Arg548Trp Uncertain significance ★★ ⚠ same condition
OPTN p.Arg96His Uncertain significance ★★ ⚠ 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-ile577thr (accessed [today's date]).

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