Is ACO2 p.Leu724Val (c.2170C>G) pathogenic?

ACO2 p.Leu724Val (c.2170C>G) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-30). AlphaMissense: likely benign (0.0843); Absent from gnomAD v4.1.

How common is ACO2 p.Leu724Val (c.2170C>G) in the general population?

ACO2 p.Leu724Val (c.2170C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACO2 p.Leu724Val (c.2170C>G)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

ACO2 p.Leu724Val

c.2170C>G · VCV3672143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -7.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.90	donor gain, 1 bp away · masked 0 · deltas
Pangolin	Δ0.60	gain · loss 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 0.78, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	23.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACO2
Protein: p.Leu724Val
Coding: c.2170C>G
MANE Select: NM_001098
Type: single nucleotide variant
Location: chr22:41527984 (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-leu724val (accessed [today's date]).

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