Is ACO2 p.Ile283Val (c.847A>G) pathogenic?

ACO2 p.Ile283Val (c.847A>G) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1097); Ultra-rare (popmax 0.0845%, sas).

How common is ACO2 p.Ile283Val (c.847A>G) in the general population?

ACO2 p.Ile283Val (c.847A>G) is ultra-rare (popmax 0.0845%, sas) (gnomAD).

What do computational predictors say about ACO2 p.Ile283Val (c.847A>G)?

AlphaMissense predicts likely benign (score 0.1097) — an in-silico prediction, not a clinical call.

ACO2 p.Ile283Val

c.847A>G · rs746659632 · VCV1485495

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0845%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1097	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -9.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	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	26.1	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 0.0845% South Asian · 77/91,082 alleles

Filtering AF 0.0693% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0637%

Overall 0.00527% 85/1,613,666 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0845%	1,183
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Admixed American	0.00333%	29,998
European (non-Finnish)	0.000169%	589,977

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.Ile283Val
Coding: c.847A>G
MANE Select: NM_001098
dbSNP: rs746659632
Type: single nucleotide variant
Location: chr22:41517538 (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.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
ACO2 c.2208+5G>C Uncertain significance ★★ same type
ACO2 c.2208+5G>T 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-ile283val (accessed [today's date]).

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