Is OPTN p.Gln467Pro (c.1400A>C) pathogenic?

OPTN p.Gln467Pro (c.1400A>C) is classified Likely pathogenic in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-09). AlphaMissense: likely pathogenic (0.9851); Very rare (popmax 6.2e-05%); Associated with amyotrophic lateral sclerosis type 12.

What condition is associated with OPTN p.Gln467Pro (c.1400A>C)?

OPTN p.Gln467Pro (c.1400A>C) is associated with amyotrophic lateral sclerosis type 12 (ClinVar).

How common is OPTN p.Gln467Pro (c.1400A>C) in the general population?

OPTN p.Gln467Pro (c.1400A>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about OPTN p.Gln467Pro (c.1400A>C)?

AlphaMissense predicts likely pathogenic (score 0.9851) — an in-silico prediction, not a clinical call.

OPTN p.Gln467Pro

c.1400A>C · rs2131520977 · VCV1175726

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 12

Computational evidence

Protein change
AlphaMissense	0.9851	likely pathogenic ✓ concordant with ClinVar · top 2% in OPTN
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -16.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	31.0	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 6.2e-05%

Overall 6.2e-05% 1/1,613,692 alleles · very rare exomes 1/1,461,408 · genomes 0/152,284 · 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.Gln467Pro
Coding: c.1400A>C
MANE Select: NM_001008212
dbSNP: rs2131520977
Type: single nucleotide variant
Location: chr10:13127902 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 467: an α-helix; the 'interaction with hd' region; the 'interaction with myo6' region

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

Disease context

amyotrophic lateral sclerosis type 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OPTN p.Gln467Arg 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
OPTN p.Gln79Ter Pathogenic/Likely pathogenic ★★ same condition
OPTN p.Glu135Ter 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-gln467pro (accessed [today's date]).

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