Is ACO2 p.Pro330Ser (c.988C>T) pathogenic?

ACO2 p.Pro330Ser (c.988C>T) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.0675); Ultra-rare (popmax 0.0267%, afr); Associated with Inborn genetic diseases.

What condition is associated with ACO2 p.Pro330Ser (c.988C>T)?

ACO2 p.Pro330Ser (c.988C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACO2 p.Pro330Ser (c.988C>T) in the general population?

ACO2 p.Pro330Ser (c.988C>T) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

What do computational predictors say about ACO2 p.Pro330Ser (c.988C>T)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

ACO2 p.Pro330Ser

c.988C>T · rs150129663 · VCV520988

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.061	moderately benign-leaning
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 9,513 bp · p 5.1e-10 · regional, not allelic
Overall
CADD	17.76	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 0.0267% African / African-American · 20/75,026 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00186% 30/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,751
Remaining individualsnot grpmax-eligible	0.016%	6,249

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.Pro330Ser
Coding: c.988C>T
MANE Select: NM_001098
dbSNP: rs150129663
Type: single nucleotide variant
Location: chr22:41518528 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACO2 p.Pro330Leu Uncertain significance ★ ⚠ same residue
ACO2 c.1605+5G>C Uncertain significance ★★ same condition
ACO2 c.2208+5G>T Uncertain significance ★★ same condition
ACO2 p.Ala500Thr Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg141His Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg18Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg61Gln Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg633Leu Uncertain significance ★★ ⚠ same condition

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-pro330ser (accessed [today's date]).

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