Is ACO2 p.Arg684Trp (c.2050C>T) pathogenic?

ACO2 p.Arg684Trp (c.2050C>T) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.4141); Ultra-rare (popmax 0.0102%, nfe); Associated with infantile cerebellar-retinal degeneration.

What condition is associated with ACO2 p.Arg684Trp (c.2050C>T)?

ACO2 p.Arg684Trp (c.2050C>T) is associated with infantile cerebellar-retinal degeneration, optic atrophy 9 (ClinVar).

How common is ACO2 p.Arg684Trp (c.2050C>T) in the general population?

ACO2 p.Arg684Trp (c.2050C>T) is ultra-rare (popmax 0.0102%, 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.Arg684Trp (c.2050C>T)?

AlphaMissense predicts ambiguous (score 0.4141) — an in-silico prediction, not a clinical call.

ACO2 p.Arg684Trp

c.2050C>T · rs768950391 · VCV562210

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4141 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

infantile cerebellar-retinal degeneration

Computational evidence

Protein change
AlphaMissense	0.4141	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -14.18	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	26.8	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 0.0102% European (non-Finnish) · 120/1,179,918 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00775% 125/1,613,380 alleles · ultra-rare exomes 117/1,461,172 · genomes 8/152,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0102%	9,833
South Asian	0.0033%	30,347
Remaining individualsnot grpmax-eligible	0.0016%	62,436
Finnishnot grpmax-eligible	0.00156%	63,938

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.Arg684Trp
Coding: c.2050C>T
MANE Select: NM_001098
dbSNP: rs768950391
Type: single nucleotide variant
Location: chr22:41527384 (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

Also linked: optic atrophy 9

For Infantile cerebellar-retinal degeneration (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ACO2 p.Arg684Gln Uncertain significance ★★ ⚠ same residue
ACO2 p.Arg684= Likely benign ★ same residue
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.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-arg684trp (accessed [today's date]).

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