LRRD1

Summary

LRRD1 (leucine rich repeats and death domain containing 1, HGNC:34300) is a protein-coding gene on chromosome 7q21.2, encoding Leucine-rich repeat and death domain-containing protein 1 (A4D1F6).

Predicted to be involved in signal transduction. Predicted to be active in cytoplasm.

Source: NCBI Gene 401387 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 4 total — 2 pathogenic
• MANE Select transcript: NM_001161528

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:34300
Approved symbol	LRRD1
Name	leucine rich repeats and death domain containing 1
Location	7q21.2
Locus type	gene with protein product
Status	Approved
Aliases	IMAGE:4798971
Ensembl gene	ENSG00000240720
Ensembl biotype	protein_coding
Entrez	401387

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000343318, ENST00000437357, ENST00000458448

RefSeq mRNA: 4 — MANE Select: NM_001161528 NM_001161528, NM_001384932, NM_001384933, NM_001384934

CCDS: CCDS55124, CCDS94143

Canonical transcript exons

ENST00000458448 — 6 exons

Exon	Start	End
ENSE00001607657	92144842	92145074
ENSE00001686721	92146083	92146200
ENSE00001718352	92179007	92179142
ENSE00003470604	92159005	92159203
ENSE00003570110	92163286	92165276
ENSE00003601132	92150534	92150695

Expression profiles

Bgee: expression breadth broad, 74 present calls, max score 79.89.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0121 / max 9.9239, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84780	0.0121	3

Top tissues by expression

202 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.89	gold quality
left testis	UBERON:0004533	78.27	gold quality
right testis	UBERON:0004534	76.75	gold quality
testis	UBERON:0000473	75.23	gold quality
lower lobe of lung	UBERON:0008949	57.64	silver quality
cerebellar cortex	UBERON:0002129	51.50	gold quality
cerebellar hemisphere	UBERON:0002245	51.45	gold quality
buccal mucosa cell	CL:0002336	50.94	gold quality
cerebellum	UBERON:0002037	50.68	gold quality
ganglionic eminence	UBERON:0004023	50.17	silver quality
right hemisphere of cerebellum	UBERON:0014890	49.57	gold quality
ventricular zone	UBERON:0003053	49.02	gold quality
stromal cell of endometrium	CL:0002255	48.88	gold quality
bone marrow cell	CL:0002092	47.50	gold quality
endometrium	UBERON:0001295	46.63	silver quality
hypothalamus	UBERON:0001898	46.36	gold quality
islet of Langerhans	UBERON:0000006	44.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	44.55	silver quality
right ovary	UBERON:0002118	44.48	gold quality
adenohypophysis	UBERON:0002196	44.34	gold quality
cortical plate	UBERON:0005343	43.98	gold quality
left ovary	UBERON:0002119	43.97	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
ovary	UBERON:0000992	43.35	silver quality
pituitary gland	UBERON:0000007	42.98	silver quality
trachea	UBERON:0003126	42.98	gold quality
uterus	UBERON:0000995	42.80	silver quality
prefrontal cortex	UBERON:0000451	42.67	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
anterior cingulate cortex	UBERON:0009835	42.53	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	39.69
E-ANND-3	no	3.58

Regulation

Is transcription factor: no

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lrrd1	ENSMUSG00000040367
rattus_norvegicus	Lrrd1	ENSRNOG00000026196

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), PHLPP1 (ENSG00000081913), SHOC2 (ENSG00000108061), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC8A (ENSG00000136802), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRK1 (ENSG00000154237), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8C (ENSG00000171488), LRRC8D (ENSG00000171492), PIDD1 (ENSG00000177595), SCRIB (ENSG00000180900), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954)

Protein

Protein identifiers

Leucine-rich repeat and death domain-containing protein 1 — A4D1F6 (reviewed: A4D1F6)

All UniProt accessions (2): A4D1F6, C9K0I1

Isoforms (2)

UniProt ID	Names	Canonical?
A4D1F6-1	1	yes
A4D1F6-2	2

RefSeq proteins (4): NP_001155000, NP_001371861, NP_001371862, NP_001371863 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family
IPR055414	LRR_R13L4/SHOC2-like	Domain
IPR056869	DD_LRRD1	Domain

Pfam: PF00560, PF13855, PF23598, PF24978

UniProt features (35 total): repeat 27, compositionally biased region 2, splice variant 2, chain 1, domain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A4D1F6-F1	81.53	0.62

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 8 (showing top): CHAMP1_TARGET_GENES, ZNF561_TARGET_GENES, ZSCAN30_TARGET_GENES, ZNF140_TARGET_GENES, NIKOLSKY_BREAST_CANCER_7Q21_Q22_AMPLICON, chr7q21, ODONNELL_TFRC_TARGETS_UP, GSE21927_SPLENIC_C26GM_TUMOROUS_VS_4T1_TUMOR_MONOCYTES_UP

GO Biological Process (1): signal transduction (GO:0007165)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRD1	ANKIB1	Q9P2G1	431
LRRD1	CYP51A1	Q16850	326
LRRD1	KRIT1	O00522	253
LRRD1	STYX	Q8WUJ0	251
LRRD1	FAXDC2	Q96IV6	248
LRRD1	YES1	P07947	216
LRRD1	AKAP9	Q99996	213
LRRD1	CDIP1	Q9H305	207
LRRD1	PDRG1	Q9NUG6	203
LRRD1	BPTF	Q12830	195
LRRD1	PGAM5	Q96HS1	185
LRRD1	CLIP2	Q9UDT6	181
LRRD1	PTPN13	Q12923	181
LRRD1	MS4A6E	Q96DS6	176
LRRD1	CCAR1	Q8IX12	170

IntAct

4 interactions, top by confidence:

A	B	Type	Score
LRRD1	PRKCSH	psi-mi:“MI:0915”(physical association)	0.400
NS1	LRRD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): LRRD1 (Synthetic Lethality), PRKCSH (Proximity Label-MS), LRRD1 (Affinity Capture-MS), RNF213 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A4D1F6, A4IIK1, A6H6A4, A6NIV6, A6NM36, C0STK7, D3ZXS4, F1R6I3, F6R2G2, P14605, Q09562, Q32KX5, Q38SD2, Q3TX51, Q3UHC2, Q3UV48, Q3ZC49, Q4R6F0, Q54AX5, Q58A48, Q5G5E0, Q62192, Q65YW8, Q65Z91, Q66HD6, Q6AXL3, Q6GLE8, Q6GM71, Q6R5N8, Q6ZNQ3, Q7Z2Q7, Q86X40, Q8BGI7, Q8C0R9, Q8N456, Q8VDB8, Q96DD0, Q99467, Q99MB1, Q9BYS8

Diamond homologs: A4D1F6, Q4R6F0, Q8C0R9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

4 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	2
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1299385	NC_000007.13:g.(91715729_91718698)_(91864237_91972337)del	Pathogenic
3245752	NC_000007.13:g.(?91502908)(91871449_?)del	Pathogenic

SpliceAI

1119 predictions. Top by Δscore:

Variant	Effect	Δscore
7:92178971:CAGGG:C	donor_gain	1.0000
7:92145070:CAGTG:C	acceptor_gain	0.9900
7:92145075:C:CC	acceptor_gain	0.9900
7:92146213:A:C	acceptor_gain	0.9900
7:92150533:CCAT:C	donor_gain	0.9900
7:92150586:T:A	donor_gain	0.9900
7:92178970:A:AC	donor_gain	0.9900
7:92178971:C:CC	donor_gain	0.9900
7:92178994:C:CA	donor_gain	0.9900
7:92145072:GTG:G	acceptor_gain	0.9800
7:92145073:TG:T	acceptor_gain	0.9800
7:92146205:G:C	acceptor_gain	0.9800
7:92178799:T:C	donor_gain	0.9800
7:92178993:AC:A	donor_gain	0.9800
7:92146201:C:CC	acceptor_gain	0.9700
7:92145073:TGCTG:T	acceptor_loss	0.9600
7:92145074:GCTGA:G	acceptor_loss	0.9600
7:92145075:C:A	acceptor_loss	0.9600
7:92145076:T:C	acceptor_loss	0.9600
7:92146199:CT:C	acceptor_gain	0.9600
7:92145071:AGTG:A	acceptor_gain	0.9500
7:92145077:GAAAA:G	acceptor_loss	0.9500
7:92145078:AAAAA:A	acceptor_loss	0.9500
7:92145083:C:CT	acceptor_loss	0.9500
7:92145084:A:T	acceptor_loss	0.9500
7:92146212:C:CT	acceptor_gain	0.9400
7:92145079:AAAA:A	acceptor_loss	0.9300
7:92145848:G:A	donor_gain	0.9300
7:92146132:A:C	acceptor_gain	0.9300
7:92146196:TTTCT:T	acceptor_gain	0.9300

AlphaMissense

5680 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:92163850:G:C	N451K	0.986
7:92163850:G:T	N451K	0.986
7:92164004:A:G	L400P	0.986
7:92159154:A:G	L656P	0.983
7:92163935:A:G	L423P	0.983
7:92163590:A:G	L538P	0.982
7:92163314:A:G	L630P	0.981
7:92163521:A:G	L561P	0.980
7:92164073:A:G	L377P	0.980
7:92159016:A:G	L702P	0.979
7:92163452:A:G	L584P	0.979
7:92164142:A:G	L354P	0.979
7:92164057:A:C	N382K	0.978
7:92164057:A:T	N382K	0.978
7:92159069:A:C	N684K	0.974
7:92159069:A:T	N684K	0.974
7:92159079:G:T	A681E	0.974
7:92163712:A:C	N497K	0.974
7:92163712:A:T	N497K	0.974
7:92163998:A:G	L402P	0.972
7:92164280:A:G	L308P	0.972
7:92164264:G:C	N313K	0.971
7:92164264:G:T	N313K	0.971
7:92150691:A:C	N707K	0.970
7:92150691:A:T	N707K	0.970
7:92159138:A:C	N661K	0.970
7:92159138:A:T	N661K	0.970
7:92164121:A:G	L361S	0.970
7:92159154:A:T	L656H	0.969
7:92163988:A:C	N405K	0.969

dbSNP variants (sampled 300 via entrez): RS1000069436 (7:92165729 C>T), RS1000138814 (7:92157005 T>C), RS1000344867 (7:92158055 G>A), RS1000357260 (7:92180810 G>C), RS1000460682 (7:92159922 C>T), RS1000547888 (7:92145564 C>A,G,T), RS1000588427 (7:92151123 T>C), RS1000588520 (7:92173254 A>G), RS1000705297 (7:92145262 C>T), RS1000743917 (7:92158701 G>C), RS1000783614 (7:92151964 A>G), RS1000898898 (7:92151647 C>T), RS1000966627 (7:92159422 A>G), RS1001015175 (7:92145510 A>T), RS1001075542 (7:92167324 G>A)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (1): cerebral cavernous malformation (MONDO:0000820)

Orphanet (2): Familial cerebral cavernous malformation (Orphanet:221061), NON RARE IN EUROPE: Cerebral cavernous malformations (Orphanet:164)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006993_10	Hippocampal volume in Alzheimer’s disease dementia	2.000000e-07
GCST90002383_427	Hematocrit	4.000000e-17
GCST90002384_75	Hemoglobin	5.000000e-19

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005035	hippocampal volume
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	1
epigallocatechin gallate	increases expression	1
2-palmitoylglycerol	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

9 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03589014	PHASE2	COMPLETED	Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation
NCT05085561	PHASE2	COMPLETED	The Symptomatic Cerebral Cavernous Malformation Trial of REC-994
NCT02603328	PHASE1/PHASE2	COMPLETED	Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial
NCT02946866	Not specified	UNKNOWN	CoHOrt of Cerebral CavernOus maLformATion: multicEnter Prospective Observational Study
NCT03652181	Not specified	COMPLETED	CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness
NCT04467489	Not specified	ACTIVE_NOT_RECRUITING	Biomarkers of CASH
NCT05148663	Not specified	TERMINATED	CCM Blood Biomarker Validation Study
NCT05298709	Not specified	TERMINATED	Functional Magnetic Resonance Imaging (fMRI) Vascular Reactivity in Cerebral Cavernous Malformations (CCM)
NCT06983132	Not specified	RECRUITING	Natural History of Familial Cerebral Cavernous Malformations: the CCM_Italia Cohort Study