Is ACO2 p.Arg142Trp (c.424C>T) pathogenic?

ACO2 p.Arg142Trp (c.424C>T) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-19). AlphaMissense: ambiguous (0.3974); Ultra-rare (popmax 0.0329%, mid).

How common is ACO2 p.Arg142Trp (c.424C>T) in the general population?

ACO2 p.Arg142Trp (c.424C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about ACO2 p.Arg142Trp (c.424C>T)?

AlphaMissense predicts ambiguous (score 0.3974) — an in-silico prediction, not a clinical call.

ACO2 p.Arg142Trp

c.424C>T · rs779868128 · VCV937993

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3974 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3974	ambiguous
REVEL	0.709	pathogenic-leaning
SaProt	LLR -14.79	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.49	GERP 0.58, phastCons 0.055
Regional constraint	o/e 0.45	unconstrained · MANE · 7,916 bp · p 5e-15 · regional, not allelic
Overall
CADD	27.2	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 0.0329% Middle Eastern · 2/6,072 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.00218% 35/1,608,964 alleles · ultra-rare exomes 24/1,456,776 · genomes 11/152,188 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,036
African / African-American	0.0147%	6,806
Finnishnot grpmax-eligible	0.0109%	9,134
Remaining individualsnot grpmax-eligible	0.00161%	62,250
European (non-Finnish)	0.00111%	90,452
South Asian	0.0011%	90,930

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.Arg142Trp
Coding: c.424C>T
MANE Select: NM_001098
dbSNP: rs779868128
Type: single nucleotide variant
Location: chr22:41508041 (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.Arg142Gln Uncertain significance ★★ ⚠ same residue
ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Arg84Ter Pathogenic ★★ same type
ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same type
ACO2 p.Gly503Ter Pathogenic ★★ same type
ACO2 c.1605+5G>C Uncertain significance ★★ same type
ACO2 c.2208+5G>C 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/aco2-p-arg142trp (accessed [today's date]).

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