Is OPTN p.Val147Ala (c.440T>C) pathogenic?

OPTN p.Val147Ala (c.440T>C) is classified Uncertain significance in OPTN (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-03). AlphaMissense: likely benign (0.2848); Ultra-rare (popmax 0.0333%, afr); Associated with Inborn genetic diseases.

What condition is associated with OPTN p.Val147Ala (c.440T>C)?

OPTN p.Val147Ala (c.440T>C) is associated with Inborn genetic diseases (ClinVar).

How common is OPTN p.Val147Ala (c.440T>C) in the general population?

OPTN p.Val147Ala (c.440T>C) is ultra-rare (popmax 0.0333%, afr) (gnomAD).

What do computational predictors say about OPTN p.Val147Ala (c.440T>C)?

AlphaMissense predicts likely benign (score 0.2848) — an in-silico prediction, not a clinical call.

OPTN p.Val147Ala

c.440T>C · rs200863693 · VCV1740393

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2848 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2848	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -9.95	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 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 28 kb · p 0.058 · regional, not allelic
Overall
CADD	23.3	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 0.0333% African / African-American · 25/75,008 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0018% 29/1,614,070 alleles · ultra-rare exomes 20/1,461,892 · genomes 9/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0333%	3,000
European (non-Finnish)	0.000339%	295,004

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.Val147Ala
Coding: c.440T>C
MANE Select: NM_001008212
dbSNP: rs200863693
Type: single nucleotide variant
Location: chr10:13112523 (GRCh38)
Gene constraint: LOEUF 0.877 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.90 · 14 PDB
Residue 147: the 'interaction with rab8' region; an α-helix

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.Val147Leu Uncertain significance ★ ⚠ same residue
OPTN p.Val147= Conflicting classifications of pathogenicity ★ same residue
OPTN p.Val147Glu Uncertain significance ★ ⚠ 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

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-val147ala (accessed [today's date]).

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