Is OPA1 p.Val140= (c.420G>T) pathogenic?

OPA1 p.Val140= (c.420G>T) is classified Benign/Likely benign in OPA1 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.65%, mid); Associated with autosomal dominant optic atrophy, classic form.

What condition is associated with OPA1 p.Val140= (c.420G>T)?

OPA1 p.Val140= (c.420G>T) is associated with autosomal dominant optic atrophy, classic form (ClinVar).

How common is OPA1 p.Val140= (c.420G>T) in the general population?

OPA1 p.Val140= (c.420G>T) is low-frequency (popmax 1.65%, mid) (gnomAD).

How is Autosomal dominant optic atrophy, classic form inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

OPA1 p.Val140=

c.420G>T · rs35801538 · VCV95725

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.65%, mid)

Conditions

autosomal dominant optic atrophy, classic form

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.063	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.018	GERP -3.3, phastCons 0.34
Overall
CADD	4.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.65% Middle Eastern · 100/6,044 alleles

Filtering AF 1.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.36%

Overall 0.892% 14,377/1,610,888 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.65%	60
South Asian	1.45%	69
Ashkenazi Jewishnot grpmax-eligible	1.36%	74
European (non-Finnish)	0.955%	105
Remaining individualsnot grpmax-eligible	0.894%	112
Amishnot grpmax-eligible	0.768%	130
Finnishnot grpmax-eligible	0.601%	166
Admixed American	0.412%	243
African / African-American	0.155%	646
East Asian	0.00447%	22,394

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: OPA1
Protein: p.Val140=
Coding: c.420G>T
MANE Select: NM_130837
dbSNP: rs35801538
Type: single nucleotide variant
Location: chr3:193615742 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB

Full OPA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant optic atrophy, classic form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant optic atrophy, classic form (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

OPA1 p.Val140Met Uncertain significance ★★ ⚠ same residue
OPA1 p.Val140Leu Uncertain significance ★ ⚠ same residue
OPA1 c.1035+5G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.1149+1G>T Likely pathogenic ★★ same condition
OPA1 c.1230+5G>A Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.1681+1G>T Pathogenic ★★ same condition
OPA1 c.1935+1G>C Pathogenic/Likely pathogenic ★★ same condition
OPA1 c.2778+1G>A Pathogenic/Likely 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/opa1-p-val140 (accessed [today's date]).

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