Is ACO1 p.Ala395Asp (c.1184C>A) pathogenic?

ACO1 p.Ala395Asp (c.1184C>A) is classified Benign in ACO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-08). AlphaMissense: likely benign (0.1814); Common (popmax 6.47%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ACO1 p.Ala395Asp (c.1184C>A)?

AlphaMissense predicts likely benign (score 0.1814) — an in-silico prediction, not a clinical call.

ACO1 p.Ala395Asp

Q: How common is ACO1 p.Ala395Asp (c.1184C>A) in the general population?

ACO1 p.Ala395Asp (c.1184C>A) is common (popmax 6.47%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1184C>A · VCV4683379

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1814 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.47%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1814	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -8.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 45 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	20.6	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 6.47% East Asian · 2,902/44,858 alleles

Filtering AF 6.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.19%

Overall 0.2% 3,221/1,612,016 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	6.47%	15
Remaining individualsnot grpmax-eligible	0.317%	315
Middle Eastern	0.05%	2,000
South Asian	0.0484%	2,067
African / African-American	0.0253%	3,945
Admixed American	0.0183%	5,450
European (non-Finnish)	0.00373%	26,781

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.Ala395Asp
Coding: c.1184C>A
MANE Select: NM_002197
Type: single nucleotide variant
Location: chr9:32424661 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 2 PDB
Residue 395: a UniProt-annotated variant site (in)

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-ala395asp (accessed [today's date]).

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