Is ACO1 p.Val718Ile (c.2152G>A) pathogenic?

ACO1 p.Val718Ile (c.2152G>A) is classified Likely benign in ACO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0712); Ultra-rare (popmax 0.0165%, mid).

How common is ACO1 p.Val718Ile (c.2152G>A) in the general population?

ACO1 p.Val718Ile (c.2152G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACO1 p.Val718Ile (c.2152G>A)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

ACO1 p.Val718Ile

c.2152G>A · VCV4216228

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -9.02	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 4	GERP -1.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 45 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	19.32	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00727%

Overall 0.00762% 123/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.00924%	10,826
African / African-American	0.00666%	15,007
Remaining individualsnot grpmax-eligible	0.0048%	20,837
East Asian	0.00446%	22,443
Finnishnot grpmax-eligible	0.00312%	32,007
South Asian	0.0011%	91,086

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.Val718Ile
Coding: c.2152G>A
MANE Select: NM_002197
Type: single nucleotide variant
Location: chr9:32436302 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 2 PDB
Residue 718: an α-helix

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

Similar variants

ACO1 p.Val718Leu Uncertain significance ★ same residue
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

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-val718ile (accessed [today's date]).

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