Is ROBO4 p.Arg445Pro (c.1334G>C) pathogenic?

ROBO4 p.Arg445Pro (c.1334G>C) is classified Uncertain significance in ROBO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.152); Very rare (popmax 0.00136%, afr).

How common is ROBO4 p.Arg445Pro (c.1334G>C) in the general population?

ROBO4 p.Arg445Pro (c.1334G>C) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about ROBO4 p.Arg445Pro (c.1334G>C)?

AlphaMissense predicts likely benign (score 0.152) — an in-silico prediction, not a clinical call.

ROBO4 p.Arg445Pro

c.1334G>C · VCV4156057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.152 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.152	likely benign
REVEL	0.209	benign-leaning
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.7	GERP -2.6
Regional constraint	o/e 1.02	unconstrained · MANE · 13 kb · p 0.44 · regional, not allelic
Overall
CADD	17.18	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% African / African-American · 1/73,264 alleles

Filtering AF 0.000188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000123%

Overall 0.000451% 7/1,550,568 alleles · very rare exomes 5/1,398,432 · genomes 2/152,136 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00136%	73,264
European (non-Finnish)	0.000522%	191,455

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.Arg445Pro
Coding: c.1334G>C
MANE Select: NM_019055
Type: single nucleotide variant
Location: chr11:124894030 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.67

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

Similar variants

ROBO4 p.Arg445Gln Likely benign ★ same residue
ROBO4 p.Arg219His Uncertain significance ★★ ⚠ same type
ROBO4 p.Arg467Gln Uncertain significance ★★ ⚠ same type
ROBO4 p.Arg491Cys Uncertain significance ★★ ⚠ same type
ROBO4 p.Arg492Trp Uncertain significance ★★ ⚠ same type
ROBO4 p.Arg547Gln Uncertain significance ★★ ⚠ same type
ROBO4 p.Arg559Pro Uncertain significance ★★ ⚠ same type
ROBO4 p.Arg560Cys Uncertain significance ★★ ⚠ same type

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-arg445pro (accessed [today's date]).

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