Is ACO2 p.Leu74Val (c.220C>G) pathogenic?

ACO2 p.Leu74Val (c.220C>G) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-05-18). AlphaMissense: likely benign (0.1905); Rare (popmax 0.566%, nfe); Associated with infantile cerebellar-retinal degeneration.

What condition is associated with ACO2 p.Leu74Val (c.220C>G)?

ACO2 p.Leu74Val (c.220C>G) is associated with infantile cerebellar-retinal degeneration, optic atrophy, optic atrophy 9 (ClinVar).

How common is ACO2 p.Leu74Val (c.220C>G) in the general population?

ACO2 p.Leu74Val (c.220C>G) is rare (popmax 0.566%, nfe) (gnomAD).

How is Infantile cerebellar-retinal degeneration inherited?

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

What do computational predictors say about ACO2 p.Leu74Val (c.220C>G)?

AlphaMissense predicts likely benign (score 0.1905) — an in-silico prediction, not a clinical call.

ACO2 p.Leu74Val

c.220C>G · rs141772938 · VCV189310

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 18 submitters

AlphaMissense

likely benign

0.1905 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.566%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile cerebellar-retinal degeneration

Computational evidence

Protein change
AlphaMissense	0.1905	likely benign
REVEL	0.716	pathogenic-leaning
SaProt	LLR -10.32	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.73	GERP -0.71, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 39 kb · p 0.35 · regional, not allelic
Overall
CADD	21.7	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 0.566% European (non-Finnish) · 6,678/1,180,028 alleles

Filtering AF 0.555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.55%

Overall 0.461% 7,438/1,614,196 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.566%	177
Finnishnot grpmax-eligible	0.353%	283
Remaining individualsnot grpmax-eligible	0.336%	298
South Asian	0.173%	576
Admixed American	0.162%	619
African / African-American	0.0853%	1,173
Middle Eastern	0.033%	3,031
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
East Asian	0.00223%	44,888

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.Leu74Val
Coding: c.220C>G
MANE Select: NM_001098
dbSNP: rs141772938
Type: single nucleotide variant
Location: chr22:41507837 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44
Residue 74: a UniProt-annotated variant site (in opa9)

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

Disease context

infantile cerebellar-retinal degeneration — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: optic atrophy optic atrophy 9 inherited retinal dystrophy

For Infantile cerebellar-retinal degeneration (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Gly503Ter Pathogenic ★★ same condition
ACO2 p.Ala647Gly Uncertain significance ★★ ⚠ same condition
ACO2 p.Ala768Thr Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg648Cys Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Trp Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg90Trp 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/aco2-p-leu74val (accessed [today's date]).

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