Is ACO2 p.Pro3Ser (c.7C>T) pathogenic?

ACO2 p.Pro3Ser (c.7C>T) is classified Uncertain significance in ACO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-01). AlphaMissense: likely benign (0.0628); Very rare (popmax 0.0011%, sas).

How common is ACO2 p.Pro3Ser (c.7C>T) in the general population?

ACO2 p.Pro3Ser (c.7C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ACO2 p.Pro3Ser (c.7C>T)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

ACO2 p.Pro3Ser

c.7C>T · rs758749269 · VCV1518285

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -4.60	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 3.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 39 kb · p 0.35 · regional, not allelic
Overall
CADD	20.8	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 0.0011% South Asian · 1/90,644 alleles

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

Overall 0.000186% 3/1,609,796 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,644
European (non-Finnish)	0.00017%	588,998

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.Pro3Ser
Coding: c.7C>T
MANE Select: NM_001098
dbSNP: rs758749269
Type: single nucleotide variant
Location: chr22:41469153 (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.Pro3His Uncertain significance ★ ⚠ same residue
ACO2 p.Pro3= 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-pro3ser (accessed [today's date]).

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