Is ROBO2 p.Pro362Ser (c.1084C>T) pathogenic?

ROBO2 p.Pro362Ser (c.1084C>T) is classified Uncertain significance in ROBO2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-14). AlphaMissense: ambiguous (0.4064); Ultra-rare (popmax 0.0629%, afr); Associated with Inborn genetic diseases.

What condition is associated with ROBO2 p.Pro362Ser (c.1084C>T)?

ROBO2 p.Pro362Ser (c.1084C>T) is associated with Inborn genetic diseases, vesicoureteral reflux 2 (ClinVar).

How common is ROBO2 p.Pro362Ser (c.1084C>T) in the general population?

ROBO2 p.Pro362Ser (c.1084C>T) is ultra-rare (popmax 0.0629%, afr) (gnomAD).

What do computational predictors say about ROBO2 p.Pro362Ser (c.1084C>T)?

AlphaMissense predicts ambiguous (score 0.4064) — an in-silico prediction, not a clinical call.

ROBO2 p.Pro362Ser

c.1084C>T · rs757336814 · VCV2508788

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0629%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4064	ambiguous
REVEL	0.596	indeterminate
SaProt	LLR -12.21	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.44, phastCons 1
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P358S vs ClinVar P362S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0629% African / African-American · 47/74,766 alleles

Filtering AF 0.0485% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0435%

Overall 0.00316% 51/1,612,646 alleles · ultra-rare exomes 24/1,460,788 · genomes 27/151,858 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0629%	1,591
Admixed American	0.00335%	29,894
Remaining individualsnot grpmax-eligible	0.0016%	62,408
European (non-Finnish)	8.48e-05%	1,179,258

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.Pro362Ser
Coding: c.1084C>T
MANE Select: NM_001395656
dbSNP: rs757336814
Type: single nucleotide variant
Location: chr3:77550830 (GRCh38)
Gene constraint: LOEUF 0.412 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.78 · 6 PDB
Residue 358 UniProt numbering: the ig-like c2-type 4 domain

Full ROBO2 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

Also linked: vesicoureteral reflux 2

Similar variants

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.Ala1211Gly 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-pro362ser (accessed [today's date]).

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