Is ACO2 p.Ala768Thr (c.2302G>A) pathogenic?

ACO2 p.Ala768Thr (c.2302G>A) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-25). AlphaMissense: ambiguous (0.4429); Very rare (popmax 0.00153%, nfe); Associated with infantile cerebellar-retinal degeneration.

What condition is associated with ACO2 p.Ala768Thr (c.2302G>A)?

ACO2 p.Ala768Thr (c.2302G>A) is associated with infantile cerebellar-retinal degeneration (ClinVar).

How common is ACO2 p.Ala768Thr (c.2302G>A) in the general population?

ACO2 p.Ala768Thr (c.2302G>A) is very rare (popmax 0.00153%, 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.Ala768Thr (c.2302G>A)?

AlphaMissense predicts ambiguous (score 0.4429) — an in-silico prediction, not a clinical call.

ACO2 p.Ala768Thr

c.2302G>A · rs1804785 · VCV1031072

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4429 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

infantile cerebellar-retinal degeneration

Computational evidence

Protein change
AlphaMissense	0.4429	ambiguous
REVEL	0.343	indeterminate
SaProt	LLR -11.72	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	27.2	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 0.00153% European (non-Finnish) · 18/1,180,006 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00124% 20/1,612,652 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00153%	65,556
African / African-American	0.00134%	74,880
South Asian	0.0011%	91,016

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.Ala768Thr
Coding: c.2302G>A
MANE Select: NM_001098
dbSNP: rs1804785
Type: single nucleotide variant
Location: chr22:41528572 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44
Residue 768: a UniProt-annotated variant site (in)

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.Ala768Pro Uncertain significance ★ ⚠ same residue
ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Ala647Gly 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
ACO2 p.Asn197Ser 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-ala768thr (accessed [today's date]).

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