Is ROBO3 p.Pro397Ser (c.1189C>T) pathogenic?

ROBO3 p.Pro397Ser (c.1189C>T) is classified Uncertain significance in ROBO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.4191); Absent from gnomAD v4.1; Associated with gaze palsy, familial horizontal, with progressive scoliosis 1.

What condition is associated with ROBO3 p.Pro397Ser (c.1189C>T)?

ROBO3 p.Pro397Ser (c.1189C>T) is associated with gaze palsy, familial horizontal, with progressive scoliosis 1 (ClinVar).

How common is ROBO3 p.Pro397Ser (c.1189C>T) in the general population?

ROBO3 p.Pro397Ser (c.1189C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ROBO3 p.Pro397Ser (c.1189C>T)?

AlphaMissense predicts ambiguous (score 0.4191) — an in-silico prediction, not a clinical call.

ROBO3 p.Pro397Ser

Q: How is Horizontal gaze palsy with progressive scoliosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1189C>T · rs114572753 · VCV78246

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4191 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

gaze palsy, familial horizontal, with progressive scoliosis 1

Computational evidence

Protein change
AlphaMissense	0.4191	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -6.00	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.82, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	19.47	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

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: ROBO3
Protein: p.Pro397Ser
Coding: c.1189C>T
MANE Select: NM_022370
dbSNP: rs114572753
Type: single nucleotide variant
Location: chr11:124872411 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.99 · 3 PDB
Residue 397: the ig-like c2-type 4 domain

Full ROBO3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

gaze palsy, familial horizontal, with progressive scoliosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Horizontal gaze palsy with progressive scoliosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood

Similar variants

ROBO3 p.Pro397Thr Benign ★★ same residue
ROBO3 p.Pro397= Likely benign ★★ same residue
ROBO3 c.767-1G>A Pathogenic/Likely pathogenic ★★ same condition
ROBO3 p.Arg245Trp Likely pathogenic ★★ same condition
ROBO3 p.Arg703Pro Likely pathogenic ★★ same condition
ROBO3 p.Ile95Thr Likely pathogenic ★★ same condition
ROBO3 p.Pro771Leu Likely pathogenic ★★ ⚠ same condition
ROBO3 c.*67C>T 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-pro397ser (accessed [today's date]).

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