Is ROBO3 p.Ser705Pro (c.2113T>C) pathogenic?

ROBO3 p.Ser705Pro (c.2113T>C) is classified Likely pathogenic in ROBO3 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-01-09). AlphaMissense: likely pathogenic (0.9844); Absent from gnomAD v4.1; Associated with gaze palsy, familial horizontal, with progressive scoliosis 1.

What condition is associated with ROBO3 p.Ser705Pro (c.2113T>C)?

ROBO3 p.Ser705Pro (c.2113T>C) is associated with gaze palsy, familial horizontal, with progressive scoliosis 1 (ClinVar).

How common is ROBO3 p.Ser705Pro (c.2113T>C) in the general population?

ROBO3 p.Ser705Pro (c.2113T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ROBO3 p.Ser705Pro (c.2113T>C)?

AlphaMissense predicts likely pathogenic (score 0.9844) — an in-silico prediction, not a clinical call.

ROBO3 p.Ser705Pro

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.2113T>C · rs121918272 · VCV2175

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9844 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gaze palsy, familial horizontal, with progressive scoliosis 1

Computational evidence

Protein change
AlphaMissense	0.9844	likely pathogenic ✓ concordant with ClinVar · top 2% in ROBO3
REVEL	0.28	benign-leaning
SaProt	LLR -11.99	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	26.8	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.Ser705Pro
Coding: c.2113T>C
MANE Select: NM_022370
dbSNP: rs121918272
Type: single nucleotide variant
Location: chr11:124875150 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.99 · 3 PDB
Residue 705: the fibronectin type-iii 2 domain; a UniProt-annotated variant site (in hgpps1); a β-strand

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.Ser705= 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
ROBO3 p.Ala669= 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-ser705pro (accessed [today's date]).

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