Is ACO2 p.Pro62Leu (c.185C>T) pathogenic?

ACO2 p.Pro62Leu (c.185C>T) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-16). AlphaMissense: ambiguous (0.5218); Very rare (popmax 0.00223%, eas).

How common is ACO2 p.Pro62Leu (c.185C>T) in the general population?

ACO2 p.Pro62Leu (c.185C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ACO2 p.Pro62Leu (c.185C>T)?

AlphaMissense predicts ambiguous (score 0.5218) — an in-silico prediction, not a clinical call.

ACO2 p.Pro62Leu

c.185C>T · rs759393809 · VCV1810090

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Computational evidence

Protein change
AlphaMissense	0.5218	ambiguous
REVEL	0.618	indeterminate
SaProt	LLR -13.49	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.34, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 39 kb · p 0.35 · regional, not allelic
Overall
CADD	27.4	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 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,744 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
African / African-American	0.00133%	74,932
South Asian	0.0011%	91,052
European (non-Finnish)	0.000763%	131,094

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.Pro62Leu
Coding: c.185C>T
MANE Select: NM_001098
dbSNP: rs759393809
Type: single nucleotide variant
Location: chr22:41507802 (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.Pro62= 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
ACO2 c.2208+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-pro62leu (accessed [today's date]).

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