Is ROBO2 p.Pro463= (c.1389G>A) pathogenic?

ROBO2 p.Pro463= (c.1389G>A) is classified Uncertain significance in ROBO2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-23). Very rare (popmax 0.00329%, sas); Associated with vesicoureteral reflux 2.

What condition is associated with ROBO2 p.Pro463= (c.1389G>A)?

ROBO2 p.Pro463= (c.1389G>A) is associated with vesicoureteral reflux 2 (ClinVar).

How common is ROBO2 p.Pro463= (c.1389G>A) in the general population?

ROBO2 p.Pro463= (c.1389G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

ROBO2 p.Pro463=

c.1389G>A · VCV3589550

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

vesicoureteral reflux 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.57	acceptor gain · deltas
Pangolin	Δ0.48	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.7	GERP 1.2, phastCons 1
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,072 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00105% 17/1,612,976 alleles · very rare exomes 15/1,461,088 · genomes 2/151,888 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,357
African / African-American	0.00267%	37,413
Remaining individualsnot grpmax-eligible	0.0016%	62,430
European (non-Finnish)	0.000933%	107,217

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: ROBO2
Protein: p.Pro463=
Coding: c.1389G>A
MANE Select: NM_001395656
Type: single nucleotide variant
Location: chr3:77558089 (GRCh38)
Gene constraint: LOEUF 0.412 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.78 · 6 PDB
Residue 463: the ig-like c2-type 5 domain

Full ROBO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

vesicoureteral reflux 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ROBO2 p.Pro463Leu Likely benign ★★ same residue
ROBO2 c.1244-1G>A Uncertain significance ★★ same condition
ROBO2 c.3148+2T>C Uncertain significance ★★ same condition
ROBO2 p.Ala112Gly Uncertain significance ★★ same condition
ROBO2 p.Ala124= Uncertain significance ★★ same condition
ROBO2 p.Ala124Val Uncertain significance ★★ same condition
ROBO2 p.Ala556Thr Uncertain significance ★★ ⚠ same condition
ROBO2 p.Ala824Val 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/robo2-p-pro463 (accessed [today's date]).

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