Is ACO1 p.Val123Ile (c.367G>A) pathogenic?

ACO1 p.Val123Ile (c.367G>A) is classified Conflicting classifications of pathogenicity in ACO1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1329); Rare (popmax 0.28%, nfe).

How common is ACO1 p.Val123Ile (c.367G>A) in the general population?

ACO1 p.Val123Ile (c.367G>A) is rare (popmax 0.28%, nfe) (gnomAD).

What do computational predictors say about ACO1 p.Val123Ile (c.367G>A)?

AlphaMissense predicts likely benign (score 0.1329) — an in-silico prediction, not a clinical call.

ACO1 p.Val123Ile

c.367G>A · VCV3379853

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1329 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.28%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1329	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -10.21	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 45 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.28% European (non-Finnish) · 3,301/1,180,008 alleles

Filtering AF 0.272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.268%

Overall 0.224% 3,611/1,614,164 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.28%	357
Remaining individualsnot grpmax-eligible	0.202%	496
Middle Eastern	0.115%	866
Admixed American	0.0949%	1,053
South Asian	0.0736%	1,359
African / African-American	0.0586%	1,705
Finnishnot grpmax-eligible	0.0109%	9,148
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
East Asian	0.00223%	44,884

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: ACO1
Protein: p.Val123Ile
Coding: c.367G>A
MANE Select: NM_002197
Type: single nucleotide variant
Location: chr9:32408614 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 2 PDB
Residue 123: a β-strand

Full ACO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACO1 p.Ala665Val Uncertain significance ★★ ⚠ same type
ACO1 p.Arg885His Uncertain significance ★★ ⚠ same type
ACO1 p.Gly831Arg Uncertain significance ★★ ⚠ same type
ACO1 p.Ala794= Benign ★★ same type
ACO1 p.Asp569= Benign ★★ same type
ACO1 p.His252= Benign ★★ same type
ACO1 p.Pro443= Benign/Likely benign ★★ same type
ACO1 c.474+1G>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/aco1-p-val123ile (accessed [today's date]).

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