Is ACO2 p.Pro712Leu (c.2135C>T) pathogenic?

ACO2 p.Pro712Leu (c.2135C>T) is classified Conflicting classifications of pathogenicity in ACO2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-07-31). AlphaMissense: likely benign (0.1505); Ultra-rare (popmax 0.0747%, afr); Associated with ACO2-related disorder.

What condition is associated with ACO2 p.Pro712Leu (c.2135C>T)?

ACO2 p.Pro712Leu (c.2135C>T) is associated with ACO2-related disorder, infantile cerebellar-retinal degeneration (ClinVar).

How common is ACO2 p.Pro712Leu (c.2135C>T) in the general population?

ACO2 p.Pro712Leu (c.2135C>T) is ultra-rare (popmax 0.0747%, afr) (gnomAD).

What do computational predictors say about ACO2 p.Pro712Leu (c.2135C>T)?

AlphaMissense predicts likely benign (score 0.1505) — an in-silico prediction, not a clinical call.

ACO2 p.Pro712Leu

c.2135C>T · rs375761361 · VCV218317

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1505 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0747%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ACO2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1505	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -10.17	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.78, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 2,296 bp · p 4.7e-05 · regional, not allelic
Overall
CADD	29.8	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 0.0747% African / African-American · 56/74,938 alleles

Filtering AF 0.059% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0534%

Overall 0.00403% 65/1,614,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0747%	1,338
Remaining individualsnot grpmax-eligible	0.0048%	20,829
South Asian	0.00329%	30,363
Admixed American	0.00167%	59,996
European (non-Finnish)	0.000169%	590,023

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.Pro712Leu
Coding: c.2135C>T
MANE Select: NM_001098
dbSNP: rs375761361
Type: single nucleotide variant
Location: chr22:41527949 (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

ACO2-related disorder

Also linked: infantile cerebellar-retinal degeneration

Similar variants

ACO2 p.Pro712= Likely benign ★★ same residue
ACO2 p.Arg378Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Arg58Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Glu464Ter Pathogenic/Likely pathogenic ★★ same condition
ACO2 p.Ala647Gly Uncertain significance ★★ ⚠ same condition
ACO2 p.Ala768Thr Uncertain significance ★★ same condition
ACO2 p.Arg648Cys Uncertain significance ★★ ⚠ same condition
ACO2 p.Arg684Gln 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-pro712leu (accessed [today's date]).

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