Is OPTN p.Ala343Ser (c.1027G>T) pathogenic?

OPTN p.Ala343Ser (c.1027G>T) is classified Uncertain significance in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: likely benign (0.0905); Ultra-rare (popmax 0.0209%, sas); Associated with Inborn genetic diseases.

What condition is associated with OPTN p.Ala343Ser (c.1027G>T)?

OPTN p.Ala343Ser (c.1027G>T) is associated with Inborn genetic diseases (ClinVar).

How common is OPTN p.Ala343Ser (c.1027G>T) in the general population?

OPTN p.Ala343Ser (c.1027G>T) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about OPTN p.Ala343Ser (c.1027G>T)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

OPTN p.Ala343Ser

c.1027G>T · VCV4626680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -3.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 0.81, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	20.4	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 0.0209% South Asian · 19/91,066 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00118% 19/1,614,058 alleles · ultra-rare exomes 19/1,461,818 · genomes 0/152,240 · joint denominator

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.Ala343Ser
Coding: c.1027G>T
MANE Select: NM_001008212
Type: single nucleotide variant
Location: chr10:13125446 (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.Ala343= Likely benign ★ same residue
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

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-ala343ser (accessed [today's date]).

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