Is OPA1 p.Pro29Ala (c.85C>G) pathogenic?

OPA1 p.Pro29Ala (c.85C>G) is classified Conflicting classifications of pathogenicity in OPA1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.0824); Rare (popmax 0.294%, afr); Associated with mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type).

What condition is associated with OPA1 p.Pro29Ala (c.85C>G)?

OPA1 p.Pro29Ala (c.85C>G) is associated with mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type) (ClinVar).

How common is OPA1 p.Pro29Ala (c.85C>G) in the general population?

OPA1 p.Pro29Ala (c.85C>G) is rare (popmax 0.294%, afr) (gnomAD).

What do computational predictors say about OPA1 p.Pro29Ala (c.85C>G)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

OPA1 p.Pro29Ala

c.85C>G · rs145565705 · VCV496871

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.294%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type)

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2, phastCons 0.95
Overall
CADD	21.1	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 0.294% African / African-American · 221/75,050 alleles

Filtering AF 0.263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.25%

Overall 0.0169% 272/1,614,070 alleles · rare exomes 123/1,461,766 · genomes 149/152,304 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.294%	340
Admixed American	0.0333%	3,001
Remaining individualsnot grpmax-eligible	0.032%	3,125
South Asian	0.0022%	45,542
European (non-Finnish)	0.000763%	131,103

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.Pro29Ala
Coding: c.85C>G
MANE Select: NM_130837
dbSNP: rs145565705
Type: single nucleotide variant
Location: chr3:193614775 (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

mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

OPA1 p.Pro29= Likely benign ★★ same residue
OPA1 p.Pro29Gln Uncertain significance ★ ⚠ same residue
OPA1 p.Arg912Ter Pathogenic ★★ same condition
OPA1 p.Lys383Arg Pathogenic ★★ ⚠ same condition
OPA1 p.Arg810His Uncertain significance ★★ ⚠ same condition
OPA1 p.Glu576Asp Uncertain significance ★★ ⚠ same condition
OPA1 p.Gly350Glu Uncertain significance ★★ ⚠ same condition
OPA1 p.Met449Val 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/opa1-p-pro29ala (accessed [today's date]).

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