Is ACO2 p.Thr688Ser (c.2062A>T) pathogenic?

ACO2 p.Thr688Ser (c.2062A>T) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-06). AlphaMissense: ambiguous (0.3444); Ultra-rare (popmax 0.0227%, afr).

How common is ACO2 p.Thr688Ser (c.2062A>T) in the general population?

ACO2 p.Thr688Ser (c.2062A>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about ACO2 p.Thr688Ser (c.2062A>T)?

AlphaMissense predicts ambiguous (score 0.3444) — an in-silico prediction, not a clinical call.

ACO2 p.Thr688Ser

c.2062A>T · rs549853349 · VCV426151

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3444 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3444	ambiguous
REVEL	0.081	moderately benign-leaning
SaProt	LLR -8.15	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	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	25.6	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 0.0227% African / African-American · 17/75,010 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0013% 21/1,612,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,412
Remaining individualsnot grpmax-eligible	0.00481%	20,810
Admixed American	0.00167%	59,960

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.Thr688Ser
Coding: c.2062A>T
MANE Select: NM_001098
dbSNP: rs549853349
Type: single nucleotide variant
Location: chr22:41527396 (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.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
ACO2 c.2208+5G>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/aco2-p-thr688ser (accessed [today's date]).

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