Is ACO2 p.Arg10Leu (c.29G>T) pathogenic?

ACO2 p.Arg10Leu (c.29G>T) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely benign (0.2481); Very rare (popmax 8.5e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ACO2 p.Arg10Leu (c.29G>T)?

ACO2 p.Arg10Leu (c.29G>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACO2 p.Arg10Leu (c.29G>T) in the general population?

ACO2 p.Arg10Leu (c.29G>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about ACO2 p.Arg10Leu (c.29G>T)?

AlphaMissense predicts likely benign (score 0.2481) — an in-silico prediction, not a clinical call.

ACO2 p.Arg10Leu

c.29G>T · VCV3998760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2481	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -9.65	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 6.4	GERP 2.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 39 kb · p 0.35 · regional, not allelic
Overall
CADD	24.6	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 8.5e-05% European (non-Finnish) · 1/1,176,868 alleles

Overall 6.87e-05% 1/1,455,386 alleles · very rare

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.Arg10Leu
Coding: c.29G>T
MANE Select: NM_001098
Type: single nucleotide variant
Location: chr22:41469175 (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 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.Arg18Gln 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-arg10leu (accessed [today's date]).

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