Is ACO2 p.Arg633Leu (c.1898G>T) pathogenic?

ACO2 p.Arg633Leu (c.1898G>T) is classified Uncertain significance in ACO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.2329); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ACO2 p.Arg633Leu (c.1898G>T)?

ACO2 p.Arg633Leu (c.1898G>T) is associated with Inborn genetic diseases (ClinVar).

How common is ACO2 p.Arg633Leu (c.1898G>T) in the general population?

ACO2 p.Arg633Leu (c.1898G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACO2 p.Arg633Leu (c.1898G>T)?

AlphaMissense predicts likely benign (score 0.2329) — an in-silico prediction, not a clinical call.

ACO2 p.Arg633Leu

c.1898G>T · rs371183037 · VCV2797895

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2329 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2329	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -6.40	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 9.8	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	24.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACO2
Protein: p.Arg633Leu
Coding: c.1898G>T
MANE Select: NM_001098
dbSNP: rs371183037
Type: single nucleotide variant
Location: chr22:41526398 (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.Arg633Cys Uncertain significance ★ ⚠ same residue
ACO2 p.Arg633His Uncertain significance ★ ⚠ same residue
ACO2 p.Arg633= Likely benign ★ 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

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-arg633leu (accessed [today's date]).

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