Is ACO2 p.Glu421Gly (c.1262A>G) pathogenic?

ACO2 p.Glu421Gly (c.1262A>G) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-16). AlphaMissense: likely pathogenic (0.9678); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ACO2 p.Glu421Gly (c.1262A>G)?

ACO2 p.Glu421Gly (c.1262A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ACO2 p.Glu421Gly (c.1262A>G) in the general population?

ACO2 p.Glu421Gly (c.1262A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACO2 p.Glu421Gly (c.1262A>G)?

AlphaMissense predicts likely pathogenic (score 0.9678) — an in-silico prediction, not a clinical call.

ACO2 p.Glu421Gly

c.1262A>G · rs2518229795 · VCV2293846

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9678 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9678	likely pathogenic
REVEL	0.593	indeterminate
SaProt	LLR -11.51	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 11	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	31.0	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

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.Glu421Gly
Coding: c.1262A>G
MANE Select: NM_001098
dbSNP: rs2518229795
Type: single nucleotide variant
Location: chr22:41522953 (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.Glu421Lys 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.Arg18Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg61Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg633Leu 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-glu421gly (accessed [today's date]).

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