Is ACO2 p.Arg18Gln (c.53G>A) pathogenic?

ACO2 p.Arg18Gln (c.53G>A) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.161); Ultra-rare (popmax 0.0143%, sas); Associated with Inborn genetic diseases.

What condition is associated with ACO2 p.Arg18Gln (c.53G>A)?

ACO2 p.Arg18Gln (c.53G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ACO2 p.Arg18Gln (c.53G>A) in the general population?

ACO2 p.Arg18Gln (c.53G>A) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about ACO2 p.Arg18Gln (c.53G>A)?

AlphaMissense predicts likely benign (score 0.161) — an in-silico prediction, not a clinical call.

ACO2 p.Arg18Gln

c.53G>A · rs200327053 · VCV1471011

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.161 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.161	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -9.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 39 kb · p 0.35 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0143% South Asian · 13/91,050 alleles

Filtering AF 0.00845% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00661%

Overall 0.00155% 25/1,612,844 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	7,004
African / African-American	0.00267%	37,458
European (non-Finnish)	0.000847%	118,001

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.Arg18Gln
Coding: c.53G>A
MANE Select: NM_001098
dbSNP: rs200327053
Type: single nucleotide variant
Location: chr22:41499742 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACO2 p.Arg18Trp Uncertain significance ★★ ⚠ same residue
ACO2 c.1605+5G>C Uncertain significance ★★ same condition
ACO2 c.2208+5G>T Uncertain significance ★★ same condition
ACO2 p.Ala500Thr Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg141His Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg61Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg633Leu Uncertain significance ★★ ⚠ same condition
ACO2 p.Asp538Val 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-arg18gln (accessed [today's date]).

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