Is ACO2 p.Ile718Thr (c.2153T>C) pathogenic?

ACO2 p.Ile718Thr (c.2153T>C) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-09-08). AlphaMissense: likely pathogenic (0.9435); Absent from gnomAD v4.1; Associated with infantile cerebellar-retinal degeneration.

What condition is associated with ACO2 p.Ile718Thr (c.2153T>C)?

ACO2 p.Ile718Thr (c.2153T>C) is associated with infantile cerebellar-retinal degeneration (ClinVar).

How common is ACO2 p.Ile718Thr (c.2153T>C) in the general population?

ACO2 p.Ile718Thr (c.2153T>C) is absent from gnomAD v4.1 (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.Ile718Thr (c.2153T>C)?

AlphaMissense predicts likely pathogenic (score 0.9435) — an in-silico prediction, not a clinical call.

ACO2 p.Ile718Thr

c.2153T>C · rs1569026431 · VCV562211

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9435 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

infantile cerebellar-retinal degeneration

Computational evidence

Protein change
AlphaMissense	0.9435	likely pathogenic
REVEL	0.681	pathogenic-leaning
SaProt	LLR -11.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	28.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACO2
Protein: p.Ile718Thr
Coding: c.2153T>C
MANE Select: NM_001098
dbSNP: rs1569026431
Type: single nucleotide variant
Location: chr22:41527967 (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.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
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-ile718thr (accessed [today's date]).

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