Is OPA1 p.Ala758= (c.2274T>C) pathogenic?

OPA1 p.Ala758= (c.2274T>C) is classified Benign in OPA1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 57%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Behr syndrome.

OPA1 p.Ala758=

Q: What condition is associated with OPA1 p.Ala758= (c.2274T>C)?

OPA1 p.Ala758= (c.2274T>C) is associated with Behr syndrome, optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy, autosomal dominant optic atrophy, classic form (ClinVar).

Q: How common is OPA1 p.Ala758= (c.2274T>C) in the general population?

OPA1 p.Ala758= (c.2274T>C) is common (popmax 57%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2274T>C · rs9851685 · VCV95717

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 57%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

Behr syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.81	GERP -4.6, phastCons 0.015
Overall
CADD	8.525	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 57% African / African-American · 42,648/74,882 alleles

Filtering AF 56.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.3%

Overall 47.1% 759,374/1,612,978 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	57%	2
African / African-Americangrpmax	57%	2
Amishnot grpmax-eligible	56.4%	2
Ashkenazi Jewishnot grpmax-eligible	48.1%	2
Remaining individualsnot grpmax-eligible	46.9%	2
European (non-Finnish)	46.9%	2
South Asian	43.7%	2
Admixed American	42.8%	2
Middle Eastern	41.6%	2
East Asian	33.8%	3

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala758=
Coding: c.2274T>C
MANE Select: NM_130837
dbSNP: rs9851685
Type: single nucleotide variant
Location: chr3:193657175 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 758: the 'stalk region' region; the 'paddle region' region

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

Disease context

Behr syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy autosomal dominant optic atrophy, classic form mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type)

Similar variants

OPA1 p.Ala758Val 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.1935+1G>T 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-ala758 (accessed [today's date]).

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