Is ACO2 p.Trp222Arg (c.664T>C) pathogenic?

ACO2 p.Trp222Arg (c.664T>C) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-12). AlphaMissense: likely pathogenic (0.9993); Very rare (popmax 8.48e-05%, nfe); Associated with optic atrophy 9.

What condition is associated with ACO2 p.Trp222Arg (c.664T>C)?

ACO2 p.Trp222Arg (c.664T>C) is associated with optic atrophy 9 (ClinVar).

How common is ACO2 p.Trp222Arg (c.664T>C) in the general population?

ACO2 p.Trp222Arg (c.664T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ACO2 p.Trp222Arg (c.664T>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

ACO2 p.Trp222Arg

c.664T>C · VCV3897935

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

optic atrophy 9

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 2% in ACO2
REVEL	0.728	pathogenic-leaning
SaProt	LLR -14.42	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 7,916 bp · p 5e-15 · regional, not allelic
Overall
CADD	32.0	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 8.48e-05% European (non-Finnish) · 1/1,179,186 alleles

Overall 6.2e-05% 1/1,612,480 alleles · very rare exomes 1/1,460,306 · genomes 0/152,174 · joint denominator

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.Trp222Arg
Coding: c.664T>C
MANE Select: NM_001098
Type: single nucleotide variant
Location: chr22:41515515 (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

optic atrophy 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACO2 p.Trp222Ter Pathogenic ★ same residue
ACO2 p.Gly503Ter Pathogenic ★★ same condition
ACO2 p.Arg684Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Trp Uncertain significance ★★ ⚠ same condition
ACO2 p.Glu321Lys Uncertain significance ★★ ⚠ same condition
ACO2 p.Gly240Ala Uncertain significance ★★ ⚠ same condition
ACO2 c.1032+17C>T Benign ★★ same condition
ACO2 c.1370+48A>G Benign ★★ 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-trp222arg (accessed [today's date]).

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