Is ACO2 p.Arg671Trp (c.2011C>T) pathogenic?

ACO2 p.Arg671Trp (c.2011C>T) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: likely pathogenic (0.9987); Very rare (popmax 0.00133%, afr).

How common is ACO2 p.Arg671Trp (c.2011C>T) in the general population?

ACO2 p.Arg671Trp (c.2011C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACO2 p.Arg671Trp (c.2011C>T)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

ACO2 p.Arg671Trp

c.2011C>T · rs377518755 · VCV916188

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 5% in ACO2
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -8.78	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.59, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	29.5	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 · 1/75,044 alleles

Overall 6.84e-05% 1/1,461,814 alleles · very rare

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.Arg671Trp
Coding: c.2011C>T
MANE Select: NM_001098
dbSNP: rs377518755
Type: single nucleotide variant
Location: chr22:41527345 (GRCh38)
Gene constraint: LOEUF 0.489 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 95.44
Residue 671: a binding site

Full ACO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACO2 p.Arg671Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg671trp (accessed [today's date]).

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