Is ACO2 p.Gly666Ser (c.1996G>A) pathogenic?

ACO2 p.Gly666Ser (c.1996G>A) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-13). AlphaMissense: likely pathogenic (0.9928); Very rare (popmax 0.00223%, eas).

How common is ACO2 p.Gly666Ser (c.1996G>A) in the general population?

ACO2 p.Gly666Ser (c.1996G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ACO2 p.Gly666Ser (c.1996G>A)?

AlphaMissense predicts likely pathogenic (score 0.9928) — an in-silico prediction, not a clinical call.

ACO2 p.Gly666Ser

c.1996G>A · rs1205084786 · VCV2776223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9928	likely pathogenic
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -14.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.63, 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

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,878 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,836 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	0.000169%	590,009

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.Gly666Ser
Coding: c.1996G>A
MANE Select: NM_001098
dbSNP: rs1205084786
Type: single nucleotide variant
Location: chr22:41527330 (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.Gly666Asp Uncertain significance ★ same residue
ACO2 p.Gly666= Likely benign ★ 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

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-gly666ser (accessed [today's date]).

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