Is ACO2 p.Leu26= (c.76C>T) pathogenic?

ACO2 p.Leu26= (c.76C>T) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2016-01-01). Very rare (popmax 0.00133%, afr); Associated with acute intermittent porphyria.

What condition is associated with ACO2 p.Leu26= (c.76C>T)?

ACO2 p.Leu26= (c.76C>T) is associated with acute intermittent porphyria, neurodegenerative disease, optic atrophy 9 (ClinVar).

How common is ACO2 p.Leu26= (c.76C>T) in the general population?

ACO2 p.Leu26= (c.76C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Acute intermittent porphyria inherited?

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

ACO2 p.Leu26=

c.76C>T · rs1057518832 · VCV374008

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

acute intermittent porphyria

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 0.8	GERP 0.64, phastCons 1
Overall
CADD	9.406	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,938 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,720 alleles · very rare exomes 4/1,461,504 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,938
European (non-Finnish)	0.000339%	295,011

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: ACO2
Protein: p.Leu26=
Coding: c.76C>T
MANE Select: NM_001098
dbSNP: rs1057518832
Type: single nucleotide variant
Location: chr22:41499765 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44

Full ACO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acute intermittent porphyria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neurodegenerative disease optic atrophy 9

For Acute intermittent porphyria (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

ACO2 p.Gly503Ter Pathogenic ★★ same condition
ACO2 p.Arg684Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Trp Uncertain significance ★★ ⚠ same condition
ACO2 p.Glu321Lys Uncertain significance ★★ ⚠ same condition
ACO2 p.Gly240Ala Uncertain significance ★★ ⚠ same condition
ACO2 c.1032+17C>T Benign ★★ same condition
ACO2 c.1370+48A>G Benign ★★ same condition
ACO2 c.174-52G>T Benign ★★ 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/aco2-p-leu26 (accessed [today's date]).

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