Is ROBO4 p.Pro413= (c.1239A>G) pathogenic?

ROBO4 p.Pro413= (c.1239A>G) is classified Benign in ROBO4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-03-21). Common (popmax 8.32%, afr) — too common for a highly-penetrant pathogenic allele; Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with ROBO4 p.Pro413= (c.1239A>G)?

ROBO4 p.Pro413= (c.1239A>G) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

ROBO4 p.Pro413=

Q: How common is ROBO4 p.Pro413= (c.1239A>G) in the general population?

ROBO4 p.Pro413= (c.1239A>G) is common (popmax 8.32%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

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

c.1239A>G · rs11820142 · VCV768494

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 8.32%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

familial thoracic aortic aneurysm and aortic dissection

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 0.089	GERP 0.3, phastCons 0.97
Overall
CADD	9.616	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.32% African / African-American · 6,245/75,016 alleles

Filtering AF 8.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.08%

Overall 0.445% 7,184/1,614,060 alleles · common exomes 3,635/1,461,784 · genomes 3,549/152,276 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.32%	12
Middle Eastern	0.595%	168
Remaining individualsnot grpmax-eligible	0.573%	175
Admixed American	0.572%	175
South Asian	0.0165%	6,072
European (non-Finnish)	0.0158%	6,344
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Pro413=
Coding: c.1239A>G
MANE Select: NM_019055
dbSNP: rs11820142
Type: single nucleotide variant
Location: chr11:124894280 (GRCh38)
Gene constraint: LOEUF 0.913 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.67
Residue 413: the fibronectin type-iii 2 domain

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

ROBO4 p.Pro413Ala Uncertain significance ★ ⚠ same residue
ROBO4 p.Arg219His Uncertain significance ★★ ⚠ same condition
ROBO4 p.Arg467Gln Uncertain significance ★★ ⚠ same condition
ROBO4 p.Arg547Gln Uncertain significance ★★ ⚠ same condition
ROBO4 p.Arg559Pro Uncertain significance ★★ ⚠ same condition
ROBO4 c.3001+3G>A Benign ★★ same condition
ROBO4 p.Ala486= Benign ★★ same condition
ROBO4 p.Arg380Cys 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-pro413 (accessed [today's date]).

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