Is ACO2 p.Arg607Cys (c.1819C>T) pathogenic?

ACO2 p.Arg607Cys (c.1819C>T) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.9899); Very rare (popmax 0.00133%, afr); Associated with optic atrophy 9.

What condition is associated with ACO2 p.Arg607Cys (c.1819C>T)?

ACO2 p.Arg607Cys (c.1819C>T) is associated with optic atrophy 9, infantile cerebellar-retinal degeneration (ClinVar).

How common is ACO2 p.Arg607Cys (c.1819C>T) in the general population?

ACO2 p.Arg607Cys (c.1819C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACO2 p.Arg607Cys (c.1819C>T)?

AlphaMissense predicts likely pathogenic (score 0.9899) — an in-silico prediction, not a clinical call.

ACO2 p.Arg607Cys

c.1819C>T · rs864309499 · VCV218316

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

optic atrophy 9

Computational evidence

Protein change
AlphaMissense	0.9899	likely pathogenic
REVEL	0.623	indeterminate
SaProt	LLR -14.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	33.0	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 0.00133% African / African-American · 1/75,014 alleles

Overall 0.000205% 3/1,460,558 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,044
African / African-Americangrpmax	0.00133%	75,014
European (non-Finnish)	8.47e-05%	1,180,020

Finnish 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.Arg607Cys
Coding: c.1819C>T
MANE Select: NM_001018050 · reported on NM_001098
dbSNP: rs864309499
Type: single nucleotide variant
Location: chr22:41526319 (GRCh38)

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

Also linked: infantile cerebellar-retinal degeneration

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-arg607cys (accessed [today's date]).

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