Is ACO2 p.Gly240Asp (c.719G>A) pathogenic?

ACO2 p.Gly240Asp (c.719G>A) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-10-13). AlphaMissense: likely benign (0.2891); Very rare (popmax 0.004%, afr); Associated with infantile cerebellar-retinal degeneration.

What condition is associated with ACO2 p.Gly240Asp (c.719G>A)?

ACO2 p.Gly240Asp (c.719G>A) is associated with infantile cerebellar-retinal degeneration (ClinVar).

How common is ACO2 p.Gly240Asp (c.719G>A) in the general population?

ACO2 p.Gly240Asp (c.719G>A) is very rare (popmax 0.004%, afr) (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.Gly240Asp (c.719G>A)?

AlphaMissense predicts likely benign (score 0.2891) — an in-silico prediction, not a clinical call.

ACO2 p.Gly240Asp

c.719G>A · rs141878785 · VCV424533

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile cerebellar-retinal degeneration

Computational evidence

Protein change
AlphaMissense	0.2891	likely benign
REVEL	0.664	pathogenic-leaning
SaProt	LLR -12.45	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 9,513 bp · p 5.1e-10 · regional, not allelic
Overall
CADD	26.6	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 0.004% African / African-American · 3/74,926 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,996 alleles · very rare

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.Gly240Asp
Coding: c.719G>A
MANE Select: NM_001098
dbSNP: rs141878785
Type: single nucleotide variant
Location: chr22:41515801 (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

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

For Infantile cerebellar-retinal degeneration (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACO2 p.Gly240Ala Uncertain significance ★★ ⚠ same residue
ACO2 p.Gly240Ser Uncertain significance ★★ ⚠ same residue
ACO2 p.Glu464Ter Pathogenic/Likely 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

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-gly240asp (accessed [today's date]).

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