Is OPA1 p.Pro743= (c.2229G>A) pathogenic?

OPA1 p.Pro743= (c.2229G>A) is classified Likely benign in OPA1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-10). Very rare (popmax 0.00439%, sas).

How common is OPA1 p.Pro743= (c.2229G>A) in the general population?

OPA1 p.Pro743= (c.2229G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

OPA1 p.Pro743=

c.2229G>A · rs768448865 · VCV391681

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

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 -0.68	GERP -4.3, phastCons 0.001
Overall
CADD	11.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,060 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00174% 28/1,613,708 alleles · very rare exomes 25/1,461,642 · genomes 3/152,066 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,825
South Asiangrpmax	0.00439%	22,765
East Asian	0.00223%	44,862
Admixed American	0.00167%	59,970
European (non-Finnish)	0.00153%	65,549
African / African-American	0.00134%	74,866

Remaining individuals 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.Pro743=
Coding: c.2229G>A
MANE Select: NM_130837
dbSNP: rs768448865
Type: single nucleotide variant
Location: chr3:193657130 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.92 (gnomAD)
Structure: AlphaFold pLDDT 74.02 · 11 PDB
Residue 743: the 'stalk region' region; the 'paddle region' region

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

Similar variants

OPA1 p.Pro743Arg Uncertain significance ★ ⚠ same residue
OPA1 p.Pro743Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
OPA1 p.Pro743Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro743 (accessed [today's date]).

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