Is ACO1 p.Ser690Gly (c.2068A>G) pathogenic?

ACO1 p.Ser690Gly (c.2068A>G) is classified Uncertain significance in ACO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: likely benign (0.1882); Ultra-rare (popmax 0.035%, amr).

How common is ACO1 p.Ser690Gly (c.2068A>G) in the general population?

ACO1 p.Ser690Gly (c.2068A>G) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about ACO1 p.Ser690Gly (c.2068A>G)?

AlphaMissense predicts likely benign (score 0.1882) — an in-silico prediction, not a clinical call.

ACO1 p.Ser690Gly

c.2068A>G · rs751450274 · VCV3137093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1882 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1882	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 45 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.035% Admixed American · 21/59,998 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00192% 31/1,614,044 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,857
Remaining individualsnot grpmax-eligible	0.0128%	7,811
African / African-American	0.00133%	74,942
European (non-Finnish)	8.47e-05%	1,179,988

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: ACO1
Protein: p.Ser690Gly
Coding: c.2068A>G
MANE Select: NM_002197
dbSNP: rs751450274
Type: single nucleotide variant
Location: chr9:32434670 (GRCh38)
Gene constraint: LOEUF 0.839 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.75 · 2 PDB
Residue 690: a β-strand

Full ACO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACO1 p.Ala665Val Uncertain significance ★★ ⚠ same type
ACO1 p.Arg885His Uncertain significance ★★ ⚠ same type
ACO1 p.Gly831Arg Uncertain significance ★★ ⚠ same type
ACO1 p.Ala794= Benign ★★ same type
ACO1 p.Asp569= Benign ★★ same type
ACO1 p.His252= Benign ★★ same type
ACO1 p.Pro443= Benign/Likely benign ★★ same type
ACO1 c.474+1G>T 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/aco1-p-ser690gly (accessed [today's date]).

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