HHIPL2

Summary

HHIPL2 (HHIP like 2, HGNC:25842) is a protein-coding gene on chromosome 1q41, encoding HHIP-like protein 2 (Q6UWX4).

Predicted to be located in extracellular region.

Source: NCBI Gene 79802 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 140 total
• MANE Select transcript: NM_024746

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25842
Approved symbol	HHIPL2
Name	HHIP like 2
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13840
Ensembl gene	ENSG00000143512
Ensembl biotype	protein_coding
OMIM	620214
Entrez	79802

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000343410, ENST00000468172, ENST00000473144, ENST00000494899

RefSeq mRNA: 1 — MANE Select: NM_024746 NM_024746

CCDS: CCDS1530

Canonical transcript exons

ENST00000343410 — 9 exons

Exon	Start	End
ENSE00000960548	222542012	222542155
ENSE00000960549	222540010	222540341
ENSE00000960550	222538648	222538774
ENSE00001660177	222547724	222548104
ENSE00001806708	222543537	222544189
ENSE00003464174	222522264	222522887
ENSE00003472316	222523612	222523694
ENSE00003673749	222531966	222532111
ENSE00003693506	222526969	222527050

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 84.83.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3538 / max 88.2048, expressed in 201 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17600	0.7291	144
17599	0.5735	144
17601	0.0444	31
17598	0.0069	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	84.83	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.81	gold quality
male germ cell	CL:0000015	82.94	silver quality
right testis	UBERON:0004534	80.58	gold quality
left testis	UBERON:0004533	80.55	gold quality
testis	UBERON:0000473	78.04	gold quality
tibia	UBERON:0000979	70.13	gold quality
right lobe of thyroid gland	UBERON:0001119	69.34	gold quality
left lobe of thyroid gland	UBERON:0001120	68.85	gold quality
tibialis anterior	UBERON:0001385	68.32	silver quality
thyroid gland	UBERON:0002046	67.16	gold quality
calcaneal tendon	UBERON:0003701	65.26	gold quality
granulocyte	CL:0000094	63.05	gold quality
stromal cell of endometrium	CL:0002255	61.82	gold quality
tendon	UBERON:0000043	59.86	gold quality
ileal mucosa	UBERON:0000331	59.72	silver quality
prostate gland	UBERON:0002367	59.46	gold quality
periodontal ligament	UBERON:0008266	59.44	gold quality
right lung	UBERON:0002167	58.49	gold quality
mucosa of transverse colon	UBERON:0004991	58.48	gold quality
minor salivary gland	UBERON:0001830	58.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	58.10	gold quality
tendon of biceps brachii	UBERON:0008188	57.77	gold quality
pancreatic ductal cell	CL:0002079	57.44	silver quality
left ovary	UBERON:0002119	57.40	gold quality
rectum	UBERON:0001052	57.33	gold quality
adenohypophysis	UBERON:0002196	56.82	gold quality
adrenal tissue	UBERON:0018303	56.73	gold quality
mouth mucosa	UBERON:0003729	55.87	gold quality
right coronary artery	UBERON:0001625	55.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting HHIPL2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-222-5P	98.75	69.17	1242
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-8055	97.62	66.09	1023
HSA-MIR-4314	97.50	67.30	1369
HSA-MIR-6806-5P	96.37	68.74	587
HSA-MIR-1298-3P	94.05	64.84	620
HSA-MIR-5091	92.36	64.51	99

Literature-anchored findings (GeneRIF, showing 1)

• HHIPL-2 was identified as a candidate gene involved in iron-related modulation of osteoblast markers. (PMID:22237814)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hhipl2	ENSDARG00000060008
mus_musculus	Hhipl2	ENSMUSG00000053461
rattus_norvegicus	Hhipl2	ENSRNOG00000056400

Paralogs (2): HHIP (ENSG00000164161), HHIPL1 (ENSG00000182218)

Protein

Protein identifiers

HHIP-like protein 2 — Q6UWX4 (reviewed: Q6UWX4)

All UniProt accessions (1): Q6UWX4

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Similarity. Belongs to the HHIP family.

RefSeq proteins (1): NP_079022* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011041	Quinoprot_gluc/sorb_DH_b-prop	Homologous_superfamily
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR012938	Glc/Sorbosone_DH	Domain
IPR018143	Folate_rcpt-like	Domain

Pfam: PF03024, PF07995

UniProt features (14 total): sequence variant 4, disulfide bond 4, signal peptide 1, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UWX4-F1	84.85	0.72

Functional residue map

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

Disulfide bonds (4): 204–546, 208–553, 424–442, 509–609

Glycosylation sites (1): 480

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 34 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, ATCTTGC_MIR31, KOYAMA_SEMA3B_TARGETS_DN, PRC1_BMI_UP.V1_DN, IL2_UP.V1_DN, KRAS.KIDNEY_UP.V1_DN, GSE13522_WT_VS_IFNG_KO_SKING_T_CRUZI_Y_STRAIN_INF_DN, MIR579_3P, MIR664B_3P, MIR4291, MIR6764_5P, MIR1915_3P, MIR556_3P, GSE1460_DP_THYMOCYTE_VS_NAIVE_CD4_TCELL_ADULT_BLOOD_DN, DESCARTES_MAIN_FETAL_PDE1C_ACSM3_POSITIVE_CELLS

GO Biological Process (0):

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

GO Cellular Component (1): extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

454 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HHIPL2	NBPF19	A0A087WUL8	447
HHIPL2	OR2T10	Q8NGZ9	447
HHIPL2	SPATA31F1	Q6ZU69	431
HHIPL2	OR52E4	Q8NGH9	418
HHIPL2	FAM177B	A6PVY3	411
HHIPL2	ISY1	Q9ULR0	398
HHIPL2	HIP1	O00291	396
HHIPL2	ZSCAN5A	Q9BUG6	379
HHIPL2	A0A0A6YYL6	A0A0A6YYL6	370
HHIPL2	NXPE2	Q96DL1	360
HHIPL2	ZBTB45	Q96K62	354
HHIPL2	FHIP1A	Q05DH4	348
HHIPL2	NALF2	O75949	324
HHIPL2	MTHFS	P49914	324
HHIPL2	BROX	Q5VW32	313

IntAct

9 interactions, top by confidence:

A	B	Type	Score
HHIPL2	ALOX5	psi-mi:“MI:0915”(physical association)	0.720
ALOX5	HHIPL2	psi-mi:“MI:0915”(physical association)	0.720
HHIPL2	UBE2O	psi-mi:“MI:0915”(physical association)	0.400
HHIPL2	CFTR	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (5): HHIPL2 (Two-hybrid), HHIPL2 (Two-hybrid), HHIPL2 (Proximity Label-MS), UBE2O (Affinity Capture-MS), HHIPL2 (PCA)

ESM2 similar proteins: A0A0D3QS98, A0A0D3QS99, A4D0V7, C5H5C4, F6Q1T7, O70309, O75354, P17405, P18084, P18424, P22413, P50747, P52850, P58242, P61642, P80747, Q04519, Q0VBD0, Q0VD19, Q13219, Q52KP5, Q58CQ9, Q5QQ51, Q5STE3, Q64687, Q6DFZ6, Q6KFX9, Q6MZW2, Q6P988, Q6UWX4, Q6YGZ1, Q6ZXD2, Q71RP1, Q812F8, Q8BJQ9, Q8C1F4, Q8C419, Q8N5D6, Q8N6G5, Q8R116

Diamond homologs: P73001, P75804, Q6UWX4, Q9D2G9, Q9SSG3, A1L0T3, A1L1V4, A1L4H1, A5PJQ2, A6H737, A7E3W2, B4F6N6, B5DF27, B8A4W9, E1C3U7, F1QQC3, F1RD85, F7J220, G3V801, M9NDE3, O08762, O43866, O70513, P16264, P21757, P21758, P30203, P30204, P30205, P56730, P58022, P58215, P70117, P85521, Q05585, Q07797, Q08380, Q08B63, Q14DK5, Q24JV9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	125
Likely benign	2
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1885 predictions. Top by Δscore:

Variant	Effect	Δscore
1:222538641:T:TA	donor_gain	1.0000
1:222538647:CCCA:C	donor_gain	1.0000
1:222542007:CTTA:C	donor_loss	1.0000
1:222542009:TACTT:T	donor_loss	1.0000
1:222542010:A:AC	donor_gain	1.0000
1:222542011:C:A	donor_loss	1.0000
1:222542011:C:CA	donor_gain	1.0000
1:222542083:ATAG:A	donor_gain	1.0000
1:222542151:TGACC:T	acceptor_gain	1.0000
1:222542152:GACC:G	acceptor_gain	1.0000
1:222542153:ACC:A	acceptor_gain	1.0000
1:222542154:CC:C	acceptor_gain	1.0000
1:222542154:CCC:C	acceptor_gain	1.0000
1:222542154:CCCT:C	acceptor_loss	1.0000
1:222542155:CC:C	acceptor_gain	1.0000
1:222542156:C:CC	acceptor_gain	1.0000
1:222542156:C:CG	acceptor_loss	1.0000
1:222542156:C:T	acceptor_gain	1.0000
1:222542157:T:G	acceptor_loss	1.0000
1:222547719:ACTAC:A	donor_loss	1.0000
1:222547721:TACCT:T	donor_loss	1.0000
1:222547722:AC:A	donor_loss	1.0000
1:222547723:C:CT	donor_loss	1.0000
1:222523610:A:AC	donor_gain	0.9900
1:222523611:C:CC	donor_gain	0.9900
1:222523611:CTGG:C	donor_gain	0.9900
1:222523641:CT:C	donor_gain	0.9900
1:222532112:C:CC	acceptor_gain	0.9900
1:222535101:A:AC	donor_gain	0.9900
1:222535102:C:CC	donor_gain	0.9900

AlphaMissense

4733 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:222540070:A:G	W464R	0.998
1:222540070:A:T	W464R	0.998
1:222540204:C:A	R419M	0.998
1:222540068:C:A	W464C	0.997
1:222540068:C:G	W464C	0.997
1:222540190:A:G	C424R	0.997
1:222540204:C:G	R419T	0.997
1:222540196:A:G	W422R	0.996
1:222540196:A:T	W422R	0.996
1:222540134:A:C	C442W	0.995
1:222540135:C:T	C442Y	0.995
1:222540200:G:C	N420K	0.995
1:222540200:G:T	N420K	0.995
1:222542120:T:G	H337P	0.995
1:222538726:A:T	V500D	0.994
1:222540133:C:A	G443W	0.994
1:222540188:A:C	C424W	0.994
1:222540192:C:G	R423P	0.994
1:222540194:C:A	W422C	0.994
1:222540194:C:G	W422C	0.994
1:222540203:C:A	R419S	0.994
1:222540203:C:G	R419S	0.994
1:222540211:C:A	G417W	0.994
1:222542067:C:A	G355W	0.994
1:222542121:G:C	H337D	0.994
1:222543699:T:A	E271V	0.994
1:222532069:C:A	W540C	0.993
1:222532069:C:G	W540C	0.993
1:222538673:A:C	Y518D	0.993
1:222538709:A:C	Y506D	0.993

dbSNP variants (sampled 300 via entrez): RS1000000637 (1:222524106 G>A), RS1000095086 (1:222523766 G>A,C), RS1000182091 (1:222549840 G>A), RS1000199340 (1:222549662 A>G), RS1000353680 (1:222546318 T>C), RS1000731301 (1:222534421 A>G,T), RS1000937680 (1:222539566 A>T), RS1000979447 (1:222540832 G>A), RS1001089702 (1:222522257 G>A), RS1001260272 (1:222549329 G>A), RS1001277111 (1:222543341 A>C), RS1001383701 (1:222527324 T>TC), RS1001765563 (1:222525249 T>C), RS1001899007 (1:222545954 A>T), RS1002285069 (1:222533594 AC>A)

Disease associations

OMIM: gene MIM:620214 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003995_18	Tonsillectomy	7.000000e-11
GCST005014_34	Tonsillectomy	7.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007924	tonsillectomy risk measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment	5
Phenylmercuric Acetate	affects cotreatment, increases expression	2
propionaldehyde	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
epigallocatechin gallate	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	increases expression	1
Azathioprine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Caffeine	decreases expression	1
Calcitriol	affects cotreatment, increases expression	1
Estradiol	increases expression, affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Silicon Dioxide	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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