Is OPTN p.Leu313Phe (c.937C>T) pathogenic?

OPTN p.Leu313Phe (c.937C>T) is classified Uncertain significance in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-13). AlphaMissense: likely pathogenic (0.8544); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with OPTN p.Leu313Phe (c.937C>T)?

OPTN p.Leu313Phe (c.937C>T) is associated with Inborn genetic diseases (ClinVar).

How common is OPTN p.Leu313Phe (c.937C>T) in the general population?

OPTN p.Leu313Phe (c.937C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about OPTN p.Leu313Phe (c.937C>T)?

AlphaMissense predicts likely pathogenic (score 0.8544) — an in-silico prediction, not a clinical call.

OPTN p.Leu313Phe

c.937C>T · rs376024431 · VCV3204444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8544 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8544	likely pathogenic
REVEL	0.511	indeterminate
SaProt	LLR -11.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OPTN
Protein: p.Leu313Phe
Coding: c.937C>T
MANE Select: NM_001008212
dbSNP: rs376024431
Type: single nucleotide variant
Location: chr10:13124049 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB

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-leu313phe (accessed [today's date]).

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