Is ROBO3 p.Arg288Pro (c.863G>C) pathogenic?

ROBO3 p.Arg288Pro (c.863G>C) is classified Uncertain significance in ROBO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.6521); Very rare (popmax 0.00119%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ROBO3 p.Arg288Pro (c.863G>C)?

ROBO3 p.Arg288Pro (c.863G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ROBO3 p.Arg288Pro (c.863G>C) in the general population?

ROBO3 p.Arg288Pro (c.863G>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about ROBO3 p.Arg288Pro (c.863G>C)?

AlphaMissense predicts likely pathogenic (score 0.6521) — an in-silico prediction, not a clinical call.

ROBO3 p.Arg288Pro

c.863G>C · VCV3947096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6521	likely pathogenic
REVEL	0.216	benign-leaning
SaProt	LLR -12.13	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.21	GERP -3.4
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	11.96	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 0.00119% European (non-Finnish) · 14/1,179,884 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000929% 15/1,613,976 alleles · very rare exomes 15/1,461,696 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00119%	84,277
South Asian	0.0011%	91,082

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: ROBO3
Protein: p.Arg288Pro
Coding: c.863G>C
MANE Select: NM_022370
Type: single nucleotide variant
Location: chr11:124870261 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.99 · 3 PDB
Residue 288: the ig-like c2-type 3 domain

Full ROBO3 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

ROBO3 p.Arg1296Gly Uncertain significance ★★ ⚠ same condition
ROBO3 p.Arg1365Trp Uncertain significance ★★ ⚠ same condition
ROBO3 p.Arg262His Uncertain significance ★★ ⚠ same condition
ROBO3 p.Arg603His Uncertain significance ★★ ⚠ same condition
ROBO3 p.Arg648His Uncertain significance ★★ ⚠ same condition
ROBO3 p.Asn986Ser Uncertain significance ★★ ⚠ same condition
ROBO3 p.Glu977Asp Uncertain significance ★★ ⚠ same condition
ROBO3 p.Gly431Asp 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/robo3-p-arg288pro (accessed [today's date]).

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