Is ACO2 p.Val163Leu (c.487G>T) pathogenic?

ACO2 p.Val163Leu (c.487G>T) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-13). AlphaMissense: ambiguous (0.4573); Ultra-rare (popmax 0.0251%, amr); Associated with ACO2-related disorder.

What condition is associated with ACO2 p.Val163Leu (c.487G>T)?

ACO2 p.Val163Leu (c.487G>T) is associated with ACO2-related disorder (ClinVar).

How common is ACO2 p.Val163Leu (c.487G>T) in the general population?

ACO2 p.Val163Leu (c.487G>T) is ultra-rare (popmax 0.0251%, amr) (gnomAD).

What do computational predictors say about ACO2 p.Val163Leu (c.487G>T)?

AlphaMissense predicts ambiguous (score 0.4573) — an in-silico prediction, not a clinical call.

ACO2 p.Val163Leu

c.487G>T · rs759920667 · VCV214016

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4573 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0251%, amr)

Conditions

ACO2-related disorder

Computational evidence

Protein change
AlphaMissense	0.4573	ambiguous
REVEL	0.406	indeterminate
SaProt	LLR -8.39	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 7,916 bp · p 5e-15 · regional, not allelic
Overall
CADD	23.2	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 0.0251% Admixed American · 15/59,704 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.00596% 96/1,611,234 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.166%	602
Admixed Americangrpmax	0.0251%	3,980
Remaining individualsnot grpmax-eligible	0.0192%	5,198
African / African-American	0.00268%	37,362
European (non-Finnish)	0.00153%	65,499

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val163Leu
Coding: c.487G>T
MANE Select: NM_001098
dbSNP: rs759920667
Type: single nucleotide variant
Location: chr22:41511930 (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

ACO2-related disorder

Similar variants

ACO2 p.Val163Met Uncertain significance ★★ ⚠ same residue
ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 c.1032+1G>C Likely pathogenic ★ same condition
ACO2 c.1032+2T>G Likely pathogenic ★ same condition
ACO2 c.37-2A>G Likely pathogenic ★ same condition
ACO2 c.941-1G>A Likely pathogenic ★ same condition
ACO2 c.941-1G>T Likely pathogenic ★ 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-val163leu (accessed [today's date]).

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