Is OPA1 p.Ile656Val (c.1966A>G) pathogenic?

OPA1 p.Ile656Val (c.1966A>G) is classified Uncertain significance in OPA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-15). AlphaMissense: likely benign (0.3107); Very rare (popmax 0.00221%, nfe).

How common is OPA1 p.Ile656Val (c.1966A>G) in the general population?

OPA1 p.Ile656Val (c.1966A>G) is very rare (popmax 0.00221%, nfe) (gnomAD).

What do computational predictors say about OPA1 p.Ile656Val (c.1966A>G)?

AlphaMissense predicts likely benign (score 0.3107) — an in-silico prediction, not a clinical call.

OPA1 p.Ile656Val

c.1966A>G · rs769460409 · VCV2160679

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3107 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3107	likely benign
REVEL	0.514	indeterminate
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Overall
CADD	23.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I601V vs ClinVar I656V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00221% European (non-Finnish) · 26/1,175,226 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00131%

Overall 0.00168% 27/1,608,268 alleles · very rare exomes 26/1,456,122 · genomes 1/152,146 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00221%	45,201
Remaining individualsnot grpmax-eligible	0.00161%	62,286

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.Ile656Val
Coding: c.1966A>G
MANE Select: NM_130837
dbSNP: rs769460409
Type: single nucleotide variant
Location: chr3:193648825 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 601 UniProt numbering: the 'stalk region' region

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

Similar variants

OPA1 c.1035+1G>A Pathogenic ★★ same type
OPA1 c.1035+5G>A Pathogenic/Likely pathogenic ★★ same type
OPA1 c.1149+1G>A Pathogenic ★★ same type
OPA1 c.1149+1G>T Likely pathogenic ★★ same type
OPA1 c.1150-2A>G Pathogenic ★★ same type
OPA1 c.1230+1G>A Pathogenic ★★ same type
OPA1 c.1230+5G>A Pathogenic/Likely pathogenic ★★ same type
OPA1 c.1305+1G>T Pathogenic ★★ same type

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-ile656val (accessed [today's date]).

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