R3HDML

Summary

R3HDML (R3H domain containing like, HGNC:16249) is a protein-coding gene on chromosome 20q13.12, encoding Peptidase inhibitor R3HDML (Q9H3Y0). Putative serine protease inhibitor.

Predicted to enable peptidase inhibitor activity. Predicted to be located in extracellular region. Predicted to be active in extracellular space.

Source: NCBI Gene 140902 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 45 total — 1 pathogenic
• MANE Select transcript: NM_178491

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16249
Approved symbol	R3HDML
Name	R3H domain containing like
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	dJ881L22.3
Ensembl gene	ENSG00000101074
Ensembl biotype	protein_coding
Entrez	140902

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000217043

RefSeq mRNA: 1 — MANE Select: NM_178491 NM_178491

CCDS: CCDS13329

Canonical transcript exons

ENST00000217043 — 5 exons

Exon	Start	End
ENSE00000662232	44337043	44337418
ENSE00000662233	44341196	44341314
ENSE00000662234	44343377	44343509
ENSE00000662235	44345263	44345378
ENSE00000844865	44350660	44351238

Expression profiles

Bgee: expression breadth broad, 31 present calls, max score 95.55.

Top tissues by expression

122 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	95.55	gold quality
mucosa of transverse colon	UBERON:0004991	66.11	gold quality
right uterine tube	UBERON:0001302	63.95	gold quality
rectum	UBERON:0001052	60.30	gold quality
colonic epithelium	UBERON:0000397	56.11	gold quality
transverse colon	UBERON:0001157	55.40	gold quality
duodenum	UBERON:0002114	54.61	gold quality
small intestine	UBERON:0002108	48.11	gold quality
small intestine Peyer’s patch	UBERON:0003454	47.89	gold quality
right lobe of liver	UBERON:0001114	45.43	gold quality
liver	UBERON:0002107	44.39	silver quality
intestine	UBERON:0000160	44.18	gold quality
sural nerve	UBERON:0015488	43.47	gold quality
colon	UBERON:0001155	42.64	gold quality
adult mammalian kidney	UBERON:0000082	40.16	gold quality
lower esophagus mucosa	UBERON:0035834	40.05	gold quality
kidney	UBERON:0002113	39.07	gold quality
endocervix	UBERON:0000458	37.46	silver quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
fallopian tube	UBERON:0003889	35.12	gold quality
skeletal muscle tissue	UBERON:0001134	34.81	gold quality
cortex of kidney	UBERON:0001225	33.76	gold quality
muscle tissue	UBERON:0002385	33.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
hypothalamus	UBERON:0001898	32.04	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
stomach	UBERON:0000945	30.40	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.13

Regulation

Is transcription factor: no

Cross-species orthologs

47 orthologs

Organism	Symbol	Gene ID
danio_rerio	r3hdml	ENSDARG00000030650
mus_musculus	R3hdml	ENSMUSG00000078949
rattus_norvegicus	R3hdml	ENSRNOG00000027432
drosophila_melanogaster	Ag5r	FBGN0015010
drosophila_melanogaster	Ag5r2	FBGN0020508
drosophila_melanogaster	CG9400	FBGN0030562
drosophila_melanogaster	CG10651	FBGN0032853
drosophila_melanogaster	CG9822	FBGN0034623
drosophila_melanogaster	CG17974	FBGN0034624
drosophila_melanogaster	CG3640	FBGN0035042
drosophila_melanogaster	CG8072	FBGN0036070
drosophila_melanogaster	CG6628	FBGN0036072
drosophila_melanogaster	scpr-C	FBGN0037879
drosophila_melanogaster	scpr-B	FBGN0037888
drosophila_melanogaster	scpr-A	FBGN0037889
drosophila_melanogaster	CG8483	FBGN0038126
drosophila_melanogaster	CG30486	FBGN0050486
drosophila_melanogaster	antr	FBGN0050488
drosophila_melanogaster	CG31286	FBGN0051286
drosophila_melanogaster	CG32313	FBGN0052313
drosophila_melanogaster	CG32679	FBGN0052679
drosophila_melanogaster	CG34002	FBGN0054002
drosophila_melanogaster	CG17575	FBGN0250842
drosophila_melanogaster	CG42564	FBGN0260766
drosophila_melanogaster	CG42780	FBGN0261848
drosophila_melanogaster	CG43775	FBGN0264297
drosophila_melanogaster	CG43776	FBGN0264298
drosophila_melanogaster	CG43777	FBGN0264299
caenorhabditis_elegans		WBGENE00004742
caenorhabditis_elegans		WBGENE00007397
caenorhabditis_elegans		WBGENE00008027
caenorhabditis_elegans		WBGENE00008028
caenorhabditis_elegans		WBGENE00008029
caenorhabditis_elegans		WBGENE00008030
caenorhabditis_elegans		WBGENE00008625
caenorhabditis_elegans		WBGENE00009891
caenorhabditis_elegans		WBGENE00009895
caenorhabditis_elegans		WBGENE00009896
caenorhabditis_elegans		WBGENE00012816
caenorhabditis_elegans		WBGENE00013971
caenorhabditis_elegans		WBGENE00013972
caenorhabditis_elegans		WBGENE00015246
caenorhabditis_elegans		WBGENE00017055
caenorhabditis_elegans		WBGENE00017183
caenorhabditis_elegans		WBGENE00019178
caenorhabditis_elegans		WBGENE00019179
caenorhabditis_elegans		WBGENE00021780

Paralogs (13): CRISP3 (ENSG00000096006), CRISPLD2 (ENSG00000103196), CRISPLD1 (ENSG00000121005), GLIPR2 (ENSG00000122694), CRISP2 (ENSG00000124490), CRISP1 (ENSG00000124812), PI15 (ENSG00000137558), GLIPR1 (ENSG00000139278), CLEC18B (ENSG00000140839), CLEC18A (ENSG00000157322), CLEC18C (ENSG00000157335), GLIPR1L1 (ENSG00000173401), GLIPR1L2 (ENSG00000180481)

Protein

Protein identifiers

Peptidase inhibitor R3HDML — Q9H3Y0 (reviewed: Q9H3Y0)

Alternative names: Cysteine-rich secretory protein R3HDML

All UniProt accessions (1): Q9H3Y0

UniProt curated annotations — full annotation on UniProt →

Function. Putative serine protease inhibitor.

Subcellular location. Secreted.

Similarity. Belongs to the CRISP family.

RefSeq proteins (1): NP_848586* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001283	CRISP-related	Family
IPR014044	CAP_dom	Domain
IPR035940	CAP_sf	Homologous_superfamily
IPR047899	R3HDML_CAP	Domain

Pfam: PF00188

UniProt features (7 total): sequence variant 2, signal peptide 1, propeptide 1, chain 1, domain 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3Y0-F1	83.15	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1): 120

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 15 (showing top): GOMF_PEPTIDASE_REGULATOR_ACTIVITY, GOMF_ENZYME_INHIBITOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, DESCARTES_MAIN_FETAL_INTESTINAL_EPITHELIAL_CELLS, GOMF_MOLECULAR_FUNCTION_INHIBITOR_ACTIVITY, CTTTGA_LEF1_Q2, GOMF_PEPTIDASE_INHIBITOR_ACTIVITY, TGCCAAR_NF1_Q6, SMAD3_Q6, chr20q13, GSE26488_HDAC7_KO_VS_VP16_TRANSGENIC_HDAC7_KO_DOUBLE_POSITIVE_THYMOCYTE_UP, GSE34156_UNTREATED_VS_24H_NOD2_AND_TLR1_TLR2_LIGAND_TREATED_MONOCYTE_UP, GSE37532_VISCERAL_ADIPOSE_TISSUE_VS_LN_DERIVED_TCONV_CD4_TCELL_DN, GSE46606_UNSTIM_VS_CD40L_IL2_IL5_3DAY_STIMULATED_IRF4_KO_BCELL_UP, GATTGGY_NFY_Q6_01

GO Biological Process (0):

GO Molecular Function (1): peptidase inhibitor activity (GO:0030414)

GO Cellular Component (2): obsolete extracellular space (GO:0005615), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

538 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
R3HDML	FITM2	Q8N6M3	775
R3HDML	KCNK16	Q96T55	654
R3HDML	ZFAND3	Q9H8U3	621
R3HDML	GCC1	Q96CN9	609
R3HDML	MAEA	Q7L5Y9	596
R3HDML	PSMD6	Q15008	593
R3HDML	PEPD	P12955	507
R3HDML	GLIS3	Q8NEA6	507
R3HDML	C2CD4A	Q8NCU7	506
R3HDML	CDC123	O75794	476
R3HDML	C2CD4B	A6NLJ0	447
R3HDML	PAX4	O43316	447
R3HDML	C3orf22	Q8N5N4	434
R3HDML	BTBD17	A6NE02	423
R3HDML	OPTC	Q9UBM4	417

IntAct

4 interactions, top by confidence:

A	B	Type	Score
R3HDML	PLEC	psi-mi:“MI:0915”(physical association)	0.400
R3HDML	CDK7	psi-mi:“MI:0915”(physical association)	0.400
R3HDML	HSPA5	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (4): R3HDML (Proximity Label-MS), CDK7 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0A0D3QS98, A0A0D3QS99, A2A5I3, O19010, O19011, O42596, P01137, P04202, P04629, P07200, P09533, P16562, P17246, P18341, P35739, P50414, P54108, P54831, P57110, Q01974, Q38HS2, Q3KPV7, Q3UFB7, Q505J3, Q5R7Y0, Q5T4F7, Q60477, Q658N2, Q6UWX4, Q7T141, Q7TSQ1, Q80XH4, Q8BG58, Q91009, Q99JR5, Q9CXM0, Q9D2G9, Q9EQT5, Q9GZM7, Q9H3Y0

Diamond homologs: A0A218QX58, A1BQQ5, A5D8T8, A6YPK1, A8S6B6, B0VXV6, B2MVK7, B7FDI0, B7FDI1, C0ITL3, D4P2Y4, D8VNS1, F7C0L1, F8J2D4, G3CJR9, O19010, P0DMB9, P0DMT4, P0DPU0, P0DSI3, P10736, P10737, P11670, P16562, P16563, P35759, P35778, P35779, P35780, P35781, P35782, P35783, P35785, P35786, P35787, P36110, P47032, P54108, P60623, P79845

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	37
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
979733	GRCh37/hg19 20q13.12(chr20:42778133-43079191)x1	Pathogenic

SpliceAI

695 predictions. Top by Δscore:

Variant	Effect	Δscore
20:44337415:CATGG:C	donor_loss	1.0000
20:44337416:ATGG:A	donor_loss	1.0000
20:44337417:TGGTG:T	donor_loss	1.0000
20:44337418:GGTG:G	donor_loss	1.0000
20:44337419:G:GC	donor_loss	1.0000
20:44337419:G:GG	donor_gain	1.0000
20:44337420:T:G	donor_loss	1.0000
20:44341310:GGCCA:G	donor_gain	1.0000
20:44341311:GCCA:G	donor_gain	1.0000
20:44341311:GCCAG:G	donor_gain	1.0000
20:44341315:G:GG	donor_gain	1.0000
20:44345375:T:TG	donor_gain	1.0000
20:44345379:G:GG	donor_gain	1.0000
20:44337415:CATG:C	donor_gain	0.9900
20:44337416:ATG:A	donor_gain	0.9900
20:44337417:TG:T	donor_gain	0.9900
20:44337418:GG:G	donor_gain	0.9900
20:44337421:GAG:G	donor_loss	0.9900
20:44341312:CCA:C	donor_gain	0.9900
20:44341312:CCAG:C	donor_loss	0.9900
20:44341313:CAG:C	donor_loss	0.9900
20:44341314:AGT:A	donor_loss	0.9900
20:44341315:GT:G	donor_loss	0.9900
20:44341316:TGAG:T	donor_loss	0.9900
20:44341317:G:GC	donor_loss	0.9900
20:44341318:AGTGA:A	donor_loss	0.9900
20:44341319:G:A	donor_loss	0.9900
20:44345261:A:AG	acceptor_gain	0.9900
20:44345261:AGAT:A	acceptor_gain	0.9900
20:44345262:G:GG	acceptor_gain	0.9900

AlphaMissense

1670 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:44341201:G:C	W89C	0.993
20:44341201:G:T	W89C	0.993
20:44345362:T:A	C205S	0.985
20:44345363:G:C	C205S	0.985
20:44345293:T:A	C182S	0.983
20:44345294:G:C	C182S	0.983
20:44345271:G:C	W174C	0.982
20:44345271:G:T	W174C	0.982
20:44337399:C:A	A81D	0.981
20:44341244:T:A	C104S	0.981
20:44341245:G:C	C104S	0.981
20:44345279:C:T	S177F	0.979
20:44341224:C:A	A97D	0.977
20:44341199:T:A	W89R	0.976
20:44341199:T:C	W89R	0.976
20:44341223:G:C	A97P	0.976
20:44341291:G:C	Q119H	0.976
20:44341291:G:T	Q119H	0.976
20:44345363:G:A	C205Y	0.976
20:44341234:G:C	W100C	0.974
20:44341234:G:T	W100C	0.974
20:44343509:G:C	Q171H	0.974
20:44343509:G:T	Q171H	0.974
20:44350751:T:A	C241S	0.974
20:44350752:G:C	C241S	0.974
20:44341203:A:T	D90V	0.972
20:44345290:G:T	G181C	0.972
20:44345296:G:C	A183P	0.971
20:44350685:T:G	Y219D	0.970
20:44341252:G:C	W106C	0.967

dbSNP variants (sampled 300 via entrez): RS1000027733 (20:44350126 T>A), RS1000100840 (20:44351027 G>C), RS1000102731 (20:44350103 A>C,G), RS1000174398 (20:44340454 A>G), RS1000250547 (20:44344648 T>C), RS1000304322 (20:44344927 G>A,C), RS1000461972 (20:44345929 C>G,T), RS1000464048 (20:44339227 A>G), RS1000557681 (20:44351332 C>T), RS1000594349 (20:44346185 A>G), RS1000646766 (20:44346523 A>C,G), RS1000672316 (20:44340075 C>A,T), RS1000758636 (20:44340174 C>T), RS1000798613 (20:44347228 T>C), RS1001062337 (20:44335301 T>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001351_6	Type 2 diabetes	1.000000e-11
GCST003264_896	Post bronchodilator FEV1/FVC ratio	5.000000e-06
GCST007483_44	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-07
GCST007487_31	Waist-to-hip ratio adjusted for BMI (additive genetic model)	1.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004713	FEV/FVC ratio
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases methylation, increases mutagenesis	2
terbufos	increases methylation	1
Acetaminophen	decreases expression	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Silicon Dioxide	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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