Is ACO2 p.Arg564Cys (c.1690C>T) pathogenic?

ACO2 p.Arg564Cys (c.1690C>T) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.9725); Very rare (popmax 0.0011%, sas).

How common is ACO2 p.Arg564Cys (c.1690C>T) in the general population?

ACO2 p.Arg564Cys (c.1690C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACO2 p.Arg564Cys (c.1690C>T)?

AlphaMissense predicts likely pathogenic (score 0.9725) — an in-silico prediction, not a clinical call.

ACO2 p.Arg564Cys

c.1690C>T · VCV4084964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9725	likely pathogenic
REVEL	0.392	indeterminate
SaProt	LLR -16.00	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 9,513 bp · p 5.1e-10 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,070 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,770 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,070
European (non-Finnish)	0.000254%	393,328

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.Arg564Cys
Coding: c.1690C>T
MANE Select: NM_001098
Type: single nucleotide variant
Location: chr22:41525277 (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

Similar variants

ACO2 p.Arg564His Uncertain significance ★ ⚠ same residue
ACO2 p.Arg564= Likely benign ★ same residue
ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Arg84Ter Pathogenic ★★ same type
ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Gly503Ter Pathogenic ★★ same type
ACO2 c.1605+5G>C Uncertain significance ★★ same type

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-arg564cys (accessed [today's date]).

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