Is ROBO3 p.Pro91Ser (c.271C>T) pathogenic?

ROBO3 p.Pro91Ser (c.271C>T) is classified Likely pathogenic in ROBO3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-09). AlphaMissense: likely pathogenic (0.9153); Very rare (popmax 0.00017%, nfe); Associated with gaze palsy, familial horizontal, with progressive scoliosis 1.

What condition is associated with ROBO3 p.Pro91Ser (c.271C>T)?

ROBO3 p.Pro91Ser (c.271C>T) is associated with gaze palsy, familial horizontal, with progressive scoliosis 1 (ClinVar).

How common is ROBO3 p.Pro91Ser (c.271C>T) in the general population?

ROBO3 p.Pro91Ser (c.271C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ROBO3 p.Pro91Ser (c.271C>T)?

AlphaMissense predicts likely pathogenic (score 0.9153) — an in-silico prediction, not a clinical call.

ROBO3 p.Pro91Ser

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.271C>T · rs1946240450 · VCV996109

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9153 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

gaze palsy, familial horizontal, with progressive scoliosis 1

Computational evidence

Protein change
AlphaMissense	0.9153	likely pathogenic ✓ concordant with ClinVar · top 7% in ROBO3
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -13.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 16 kb · p 0.79 · regional, not allelic
Overall
CADD	29.2	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 0.00017% European (non-Finnish) · 2/1,177,816 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,607,850 alleles · very rare exomes 2/1,455,482 · genomes 0/152,368 · joint denominator

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.Pro91Ser
Coding: c.271C>T
MANE Select: NM_022370
dbSNP: rs1946240450
Type: single nucleotide variant
Location: chr11:124868912 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.99 · 3 PDB
Residue 91: the ig-like c2-type 1 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 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
ROBO3 p.Ala900Val 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-pro91ser (accessed [today's date]).

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