ROBO4 — 301 ClinVar variants

All ClinVar germline ROBO4 variants across every classification, each assembled from ClinVar, gnomAD, AlphaMissense, conservation and more. 215 flagged for review →

17 Likely pathogenic · 6 Conflicting · 24 Benign · 4 Benign/Likely benign · 32 Likely benign · 218 Uncertain significance

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

⚑ Evidence disagreements 215

Variants where the independent computational evidence doesn't line up with the clinical picture — a QC signal for a second look, not a reclassification.

Predictors vs ClinVar 5

ClinVar calls these pathogenic, but the computational predictors lean tolerated — the highest-value review flag.

ROBO4 p.Ala95Thr Likely pathogenic Single submitter
Bicuspid aortic valve
ROBO4 p.Asp622His Likely pathogenic Single submitter
Bicuspid aortic valve
ROBO4 p.His411Gln Likely pathogenic Single submitter
Bicuspid aortic valve
ROBO4 p.Val247Ala Likely pathogenic Single submitter
Bicuspid aortic valve
ROBO4 p.Val235Met Likely pathogenic No assertion criteria
thoracic aortic aneurysm

Predictors agree, ClinVar conflicts 4

ClinVar submitters conflict, but the independent predictors unanimously agree — a QC review flag, not a reclassification.

ROBO4 p.Arg634Cys Conflicting Single submitter
aortic valve disease 3
ROBO4 p.Gly183Arg Conflicting Single submitter
ROBO4 p.Gly662Asp Conflicting Single submitter
aortic valve disease 3
ROBO4 p.Thr232Met Conflicting Single submitter
Bicuspid aortic valve

Predictors lean, ClinVar uncertain 185

ClinVar classifies these uncertain (VUS), but the independent predictors unanimously lean one way — a triage signal for review, not a reclassification. · showing the 150 best-reviewed of 185

Predictors split 21

The independent predictors disagree with each other — read with care.

All ROBO4 variants

Likely pathogenic 17

c.1042_1048dup Single submitter aortic valve disease 3
c.2056+1G>T Single submitter Bicuspid aortic valve
c.3001+1G>C Single submitter aortic valve disease 3
c.679+1G>T Single submitter
p.Ala749Leu Single submitter Bicuspid aortic valve
p.Ala95Thr Single submitter Bicuspid aortic valve ⚠
p.Asp622His Single submitter Bicuspid aortic valve ⚠
p.Gly534fs Single submitter Bicuspid aortic valve
p.His411Gln Single submitter Bicuspid aortic valve ⚠
p.Leu681fs Single submitter aortic valve disease 3
p.Ser327fs Single submitter aortic valve disease 3
p.Thr826fs Single submitter
p.Tyr280Ser Single submitter Bicuspid aortic valve
p.Tyr382Ter Single submitter aortic valve disease 3
p.Val247Ala Single submitter Bicuspid aortic valve ⚠
p.Glu797Ter No assertion criteria thoracic aortic aneurysm
p.Val235Met No assertion criteria thoracic aortic aneurysm ⚠

Conflicting classifications of pathogenicity 6

p.Arg568Ter Single submitter ROBO4-related disorder
p.Arg634Cys Single submitter aortic valve disease 3 ⚠
p.Arg64Cys Single submitter Bicuspid aortic valve ⚠
p.Gly183Arg Single submitter ⚠
p.Gly662Asp Single submitter aortic valve disease 3 ⚠
p.Thr232Met Single submitter Bicuspid aortic valve ⚠

Benign 24

c.3001+3G>A Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Ala486= Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Arg12= Multiple submitters
p.Arg380Cys Multiple submitters familial thoracic aortic aneurysm and aortic dissection ⚠
p.Arg669Gln Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Gln54Arg Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Leu563Phe Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Pro413= Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Ser592Asn Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Thr969= Multiple submitters
p.Tyr319= Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Ala550= Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Arg144Trp Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Arg547Trp Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Gln293Pro Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Gly190= Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Gly2= Single submitter familial thoracic aortic aneurysm and aortic dissection
p.His215= Single submitter familial thoracic aortic aneurysm and aortic dissection
p.His490Asp Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Leu35= Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Pro760Leu Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Ser916= Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Val384Ile Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Pro718Leu No assertion criteria ROBO4-related disorder

Benign/Likely benign 4

p.Arg606His Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Arg776Cys Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Ile34= Multiple submitters familial thoracic aortic aneurysm and aortic dissection
p.Pro182= Multiple submitters familial thoracic aortic aneurysm and aortic dissection

Likely benign 32

p.Ser869= Multiple submitters
c.1149+6C>G Single submitter
c.1548-148A>C Single submitter
c.2795-18C>T Single submitter
c.680-16C>A Single submitter
p.Ala277= Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Ala926= Single submitter
p.Arg136= Single submitter
p.Arg144Gln Single submitter
p.Arg219= Single submitter
p.Arg445Gln Single submitter
p.Arg50= Single submitter
p.Arg627His Single submitter
p.Arg669Trp Single submitter
p.Arg712His Single submitter
p.Arg776His Single submitter
p.Arg96Gln Single submitter
p.Asp145= Single submitter
p.Glu509Lys Single submitter
p.Gly189Arg Single submitter
p.Ile586= Single submitter
p.Ile931Thr Single submitter
p.Leu105Pro Single submitter
p.Leu666= Single submitter
p.Pro290= Single submitter
p.Pro369= Single submitter
p.Pro952Thr Single submitter
p.Thr186= Single submitter
p.Thr457= Single submitter
p.Arg329Trp No assertion criteria ROBO4-related disorder
p.Pro700= No assertion criteria ROBO4-related disorder
p.Thr281= No assertion criteria ROBO4-related disorder

Uncertain significance 218

p.Arg219His Multiple submitters familial thoracic aortic aneurysm and aortic dissection ⚠
p.Arg467Gln Multiple submitters familial thoracic aortic aneurysm and aortic dissection ⚠
p.Arg491Cys Multiple submitters aortic valve disease 3 ⚠
p.Arg492Trp Multiple submitters aortic valve disease 3 ⚠
p.Arg547Gln Multiple submitters familial thoracic aortic aneurysm and aortic dissection ⚠
p.Arg559Pro Multiple submitters familial thoracic aortic aneurysm and aortic dissection ⚠
p.Arg560Cys Multiple submitters aortic valve disease 3 ⚠
p.Glu227Asp Multiple submitters ⚠
p.Gly414Ala Multiple submitters aortic valve disease 3 ⚠
p.Pro824Arg Multiple submitters ⚠
p.Thr724Ile Multiple submitters aortic valve disease 3 ⚠
p.Val418Met Multiple submitters ROBO4-related disorder ⚠
c.1504+2T>G Single submitter
p.Ala104Asp Single submitter ⚠
p.Ala123Thr Single submitter ⚠
p.Ala195Ser Single submitter ⚠
p.Ala197fs Single submitter aortic valve disease 3
p.Ala209Ser Single submitter
p.Ala220Thr Single submitter ⚠
p.Ala221Asp Single submitter ⚠
p.Ala239Asp Single submitter ⚠
p.Ala275Thr Single submitter ⚠
p.Ala277Ser Single submitter ⚠
p.Ala308Thr Single submitter ⚠
p.Ala409Thr Single submitter ⚠
p.Ala421Val Single submitter
p.Ala645Ser Single submitter ⚠
p.Ala749Thr Single submitter ⚠
p.Ala886Thr Single submitter ⚠
p.Ala999Thr Single submitter ⚠
p.Arg184Ser Single submitter ⚠
p.Arg222Gln Single submitter ⚠
p.Arg222Gly Single submitter ⚠
p.Arg445Pro Single submitter ⚠
p.Arg493Cys Single submitter ⚠
p.Arg530Cys Single submitter ⚠
p.Arg530His Single submitter ⚠
p.Arg559Cys Single submitter ⚠
p.Arg606Cys Single submitter ⚠
p.Arg634His Single submitter ⚠
p.Arg634Leu Single submitter ⚠
p.Arg661Gln Single submitter ⚠
p.Arg712Cys Single submitter ⚠
p.Arg861Pro Single submitter ⚠
p.Arg861Trp Single submitter ⚠
p.Arg908Gln Single submitter aortic valve disease 3 ⚠
p.Arg908Trp Single submitter ⚠
p.Arg924Ser Single submitter ⚠
p.Arg940Trp Single submitter ⚠
p.Arg971Gln Single submitter ⚠
p.Arg971Trp Single submitter ⚠
p.Asn655Ser Single submitter ⚠
p.Asn680Ile Single submitter ⚠
p.Asp1005Gly Single submitter ⚠
p.Asp101Asn Single submitter ⚠
p.Asp108Glu Single submitter ⚠
p.Asp108His Single submitter ⚠
p.Asp253Ala Single submitter ⚠
p.Asp510Val Single submitter Bicuspid aortic valve ⚠
p.Asp897Asn Single submitter familial thoracic aortic aneurysm and aortic dissection
p.Asp941Val Single submitter ⚠
p.Cys114Tyr Single submitter ⚠
p.Cys757Ser Single submitter ⚠
p.Cys994Tyr Single submitter ⚠
p.Gln103Lys Single submitter ⚠
p.Gln181Arg Single submitter ⚠
p.Gln243His Single submitter ⚠
p.Gln33Glu Single submitter ⚠
p.Gln54Glu Single submitter ⚠
p.Gln600Glu Single submitter ⚠
p.Gln728Ter Single submitter aortic valve disease 3
p.Gln731His Single submitter ⚠
p.Gln984Pro Single submitter ⚠
p.Glu166Lys Single submitter ⚠
p.Glu198_Lys199insTer Single submitter
p.Glu202Lys Single submitter ⚠
p.Glu202Val Single submitter ⚠
p.Glu300Gln Single submitter ⚠
p.Glu344Gly Single submitter ⚠
p.Glu407Lys Single submitter ⚠
p.Glu430Lys Single submitter ⚠
p.Glu452Lys Single submitter ⚠
p.Glu641Asp Single submitter ⚠
p.Glu708Asp Single submitter ⚠
p.Gly110Ser Single submitter ⚠
p.Gly159Arg Single submitter ⚠
p.Gly175Arg Single submitter ⚠
p.Gly203Glu Single submitter ⚠
p.Gly272Ser Single submitter ⚠
p.Gly294Arg Single submitter ⚠
p.Gly2Arg Single submitter ⚠
p.Gly304Asp Single submitter aortic valve disease 3 ⚠
p.Gly304Ser Single submitter ⚠
p.Gly427Val Single submitter ⚠
p.Gly475Asp Single submitter ⚠
p.Gly475Ser Single submitter ⚠
p.Gly4Glu Single submitter ⚠
p.Gly571Arg Single submitter ⚠
p.Gly571Ser Single submitter ⚠
p.Gly5Glu Single submitter ⚠
p.Gly629Glu Single submitter ⚠
p.Gly629Val Single submitter ⚠
p.Gly829Arg Single submitter ⚠
p.Gly854Ala Single submitter ⚠
p.Gly854Glu Single submitter ⚠
p.Gly920Asp Single submitter ⚠
p.Gly920Ser Single submitter aortic valve disease 3 ⚠
p.Gly975Arg Single submitter ⚠
p.His215Arg Single submitter ⚠
p.His453Arg Single submitter ⚠
p.His453Leu Single submitter ⚠
p.His453Pro Single submitter ⚠
p.His653Pro Single submitter ⚠
p.His713Leu Single submitter ⚠
p.His81Tyr Single submitter ⚠
p.Ile141Met Single submitter ⚠
p.Ile379Leu Single submitter ⚠
p.Ile471Thr Single submitter ⚠
p.Ile489Asn Single submitter ⚠
p.Ile985Phe Single submitter ⚠
p.Ile985Val Single submitter ⚠
p.Leu20Arg Single submitter ⚠
p.Leu244Pro Single submitter ⚠
p.Leu249Pro Single submitter aortic valve disease 3
p.Leu356Arg Single submitter ⚠
p.Leu387Pro Single submitter
p.Leu589Met Single submitter ⚠
p.Leu614Val Single submitter ⚠
p.Leu67Met Single submitter ⚠
p.Leu681Ile Single submitter ⚠
p.Leu698Met Single submitter aortic valve disease 3 ⚠
p.Leu702Arg Single submitter ⚠
p.Leu745Met Single submitter ⚠
p.Leu945Pro Single submitter ⚠
p.Lys199Asn Single submitter ⚠
p.Lys646Arg Single submitter ⚠
p.Met206Val Single submitter ⚠
p.Met412Thr Single submitter aortic valve disease 3 ⚠
p.Met74Thr Single submitter ⚠
p.Phe919Leu Single submitter ⚠
p.Pro160Leu Single submitter ⚠
p.Pro16Thr Single submitter ⚠
p.Pro252Leu Single submitter ⚠
p.Pro260Thr Single submitter ⚠
p.Pro276Ser Single submitter ⚠
p.Pro290Leu Single submitter ⚠
p.Pro31Gln Single submitter ⚠
p.Pro31Leu Single submitter ROBO4-related disorder ⚠
p.Pro343Gln Single submitter ⚠
p.Pro343Leu Single submitter ⚠
p.Pro413Ala Single submitter ⚠
p.Pro455Ala Single submitter ⚠
p.Pro555Ala Single submitter ⚠
p.Pro555Ser Single submitter ⚠
p.Pro597Thr Single submitter ⚠
p.Pro609Ala Single submitter ⚠
p.Pro609fs Single submitter aortic valve disease 3
p.Pro639Ser Single submitter ⚠
p.Pro700Leu Single submitter ⚠
p.Pro715Leu Single submitter ⚠
p.Pro715Ser Single submitter ⚠
p.Pro725Ser Single submitter ⚠
p.Pro735Leu Single submitter ⚠
p.Pro770Ser Single submitter ⚠
p.Pro772Leu Single submitter ⚠
p.Pro817Ser Single submitter ⚠
p.Pro939Ser Single submitter ⚠
p.Pro958Leu Single submitter ⚠
p.Pro977Leu Single submitter ⚠
p.Pro981Leu Single submitter ⚠
p.Pro997Leu Single submitter ⚠
p.Ser451Arg Single submitter ⚠
p.Ser531Phe Single submitter ⚠
p.Ser535Pro Single submitter familial thoracic aortic aneurysm and aortic dissection ⚠
p.Ser579Gly Single submitter ⚠
p.Ser591Pro Single submitter ⚠
p.Ser632Tyr Single submitter ⚠
p.Ser656Gly Single submitter ⚠
p.Ser743Thr Single submitter ⚠
p.Ser761Arg Single submitter ⚠
p.Ser780Phe Single submitter ⚠
p.Ser879Leu Single submitter ⚠
p.Ser938Phe Single submitter ⚠
p.Ser967Ile Single submitter ⚠
p.Thr122Met Single submitter ⚠
p.Thr155Ala Single submitter ⚠
p.Thr355Ile Single submitter aortic valve disease 3 ⚠
p.Thr355Pro Single submitter
p.Thr578Ser Single submitter ⚠
p.Thr62Ala Single submitter aortic valve disease 3 ⚠
p.Thr711Ala Single submitter ⚠
p.Thr727Ala Single submitter ⚠
p.Thr840Met Single submitter ⚠
p.Thr946Asn Single submitter ⚠
p.Thr969Pro Single submitter ⚠
p.Trp524Arg Single submitter familial thoracic aortic aneurysm and aortic dissection ⚠
p.Trp956Arg Single submitter ⚠
p.Trp960Arg Single submitter ⚠
p.Tyr231His Single submitter ⚠
p.Tyr582Phe Single submitter ⚠
p.Tyr830His Single submitter ⚠
p.Val149Met Single submitter ⚠
p.Val150Ala Single submitter ⚠
p.Val150Met Single submitter ⚠
p.Val240Leu Single submitter ⚠
p.Val240Met Single submitter ⚠
p.Val270Phe Single submitter ⚠
p.Val337Leu Single submitter ⚠
p.Val363Leu Single submitter aortic valve disease 3 ⚠
p.Val36Leu Single submitter ⚠
p.Val487Met Single submitter ⚠
p.Val497Leu Single submitter ⚠
p.Val693Ala Single submitter ⚠
p.Val849fs Single submitter
p.Val849Gly Single submitter ⚠
p.Val966fs Single submitter aortic valve disease 3
p.Gly127= No assertion criteria ROBO4-related disorder
p.Tyr231Asn No assertion criteria aortic valve disease 3 ⚠