Is ACO2 p.Leu381fs (c.1136dup) pathogenic?

ACO2 p.Leu381fs (c.1136dup) is classified Pathogenic/Likely pathogenic in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-12). Very rare (popmax 0.00167%, amr).

How common is ACO2 p.Leu381fs (c.1136dup) in the general population?

ACO2 p.Leu381fs (c.1136dup) is very rare (popmax 0.00167%, amr) (gnomAD).

ACO2 p.Leu381fs

c.1136dup · rs2518227349 · VCV1960221

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 9 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	GERP 0.69, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,006 alleles

Overall 6.84e-05% 1/1,461,188 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.Leu381fs
Coding: c.1136dup
MANE Select: NM_001098
dbSNP: rs2518227349
Type: Duplication
Location: chr22:41520273 (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.Leu381= Likely benign ★ same residue
ACO2 p.Ile275fs Pathogenic/Likely pathogenic ★★ same type
ACO2 c.1370+11dup Likely benign ★★ same type
ACO2 p.Arg633fs Likely pathogenic ★ same type
ACO2 p.Asn612fs Pathogenic ★ same type
ACO2 p.Asp273fs Pathogenic ★ same type
ACO2 p.Gln566fs Likely pathogenic ★ same type
ACO2 p.Ile619fs Likely pathogenic ★ 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-leu381fs (accessed [today's date]).

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