Is ACO2 p.Cys592Ter (c.1776T>A) pathogenic?

ACO2 p.Cys592Ter (c.1776T>A) is classified Pathogenic in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-01). Absent from gnomAD v4.1; Associated with infantile cerebellar-retinal degeneration.

What condition is associated with ACO2 p.Cys592Ter (c.1776T>A)?

ACO2 p.Cys592Ter (c.1776T>A) is associated with infantile cerebellar-retinal degeneration (ClinVar).

How common is ACO2 p.Cys592Ter (c.1776T>A) in the general population?

ACO2 p.Cys592Ter (c.1776T>A) 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.

ACO2 p.Cys592Ter

c.1776T>A · rs368044961 · VCV1679318

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

infantile cerebellar-retinal degeneration

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 15 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -2.9
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Cys592Ter
Coding: c.1776T>A
MANE Select: NM_001098
dbSNP: rs368044961
Type: single nucleotide variant
Location: chr22:41526276 (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.Cys592_Asp595delinsTer Pathogenic ★ same residue
ACO2 p.Cys592Arg Uncertain significance ★ same residue
ACO2 p.Cys592Tyr Uncertain significance ★ ⚠ same residue
ACO2 p.Cys592= Likely benign ★ 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

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-cys592ter (accessed [today's date]).

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