Is ROBO4 p.Pro700= (c.2100G>T) pathogenic?

ROBO4 p.Pro700= (c.2100G>T) is classified Likely benign in ROBO4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-09-13). Ultra-rare (popmax 0.0157%, nfe); Associated with ROBO4-related disorder.

What condition is associated with ROBO4 p.Pro700= (c.2100G>T)?

ROBO4 p.Pro700= (c.2100G>T) is associated with ROBO4-related disorder (ClinVar).

How common is ROBO4 p.Pro700= (c.2100G>T) in the general population?

ROBO4 p.Pro700= (c.2100G>T) is ultra-rare (popmax 0.0157%, nfe) (gnomAD).

ROBO4 p.Pro700=

c.2100G>T · rs377742325 · VCV3040164

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, nfe)

Conditions

ROBO4-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -2.9
Overall
CADD	0.18	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0157% European (non-Finnish) · 185/1,179,966 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0131%

Overall 0.0119% 192/1,613,886 alleles · ultra-rare exomes 190/1,461,758 · genomes 2/152,128 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0157%	6,378
Admixed American	0.00833%	11,998
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,894

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: ROBO4
Protein: p.Pro700=
Coding: c.2100G>T
MANE Select: NM_019055
dbSNP: rs377742325
Type: single nucleotide variant
Location: chr11:124887456 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.67
Residue 700: a UniProt-annotated variant site (in aovd3; uncertain significance)

Full ROBO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ROBO4-related disorder

Similar variants

ROBO4 p.Pro700Leu Uncertain significance ★ ⚠ same residue
ROBO4 p.Val418Met Uncertain significance ★★ ⚠ same condition
ROBO4 p.Arg568Ter Conflicting classifications of pathogenicity ★ same condition
ROBO4 p.Pro31Leu Uncertain significance ★ ⚠ same condition
ROBO4 p.Gly127= Uncertain significance same condition
ROBO4 p.Arg329Trp Likely benign same condition
ROBO4 p.Pro718Leu Benign same condition
ROBO4 p.Thr281= Likely benign 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/robo4-p-pro700 (accessed [today's date]).

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