KHNYN

Summary

KHNYN (KH and NYN domain containing, HGNC:20166) is a protein-coding gene on chromosome 14q12, encoding Protein KHNYN (O15037).

The protein encoded by this gene contains a ribonuclease NYN domain and belongs to the N4BP1 family. The protein is a cofactor for the zinc finger antiviral protein (ZAP protein) which targets viral RNA for degradation and restricts SARS-CoV-2 infection.

Source: NCBI Gene 23351 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 159 total
• MANE Select transcript: NM_015299

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20166
Approved symbol	KHNYN
Name	KH and NYN domain containing
Location	14q12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100441
Ensembl biotype	protein_coding
OMIM	619579
Entrez	23351

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 16 protein_coding, 1 retained_intron

ENST00000251343, ENST00000553935, ENST00000554268, ENST00000556255, ENST00000556510, ENST00000556842, ENST00000859089, ENST00000859090, ENST00000859091, ENST00000859092, ENST00000859093, ENST00000859094, ENST00000859095, ENST00000859096, ENST00000859097, ENST00000944610, ENST00000944611

RefSeq mRNA: 3 — MANE Select: NM_015299 NM_001290256, NM_001290257, NM_015299

CCDS: CCDS32058

Canonical transcript exons

ENST00000553935 — 8 exons

Exon	Start	End
ENSE00000654500	24431463	24432610
ENSE00000654501	24432722	24432852
ENSE00000889470	24430714	24430931
ENSE00000889472	24436072	24436179
ENSE00001526046	24429954	24430119
ENSE00003478214	24432936	24433032
ENSE00003621627	24436388	24436489
ENSE00003625998	24437036	24441843

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 94.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.8738 / max 356.9954, expressed in 1810 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139044	17.4958	1809
139045	0.3780	167

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	94.61	gold quality
mucosa of stomach	UBERON:0001199	94.28	gold quality
right ovary	UBERON:0002118	94.22	gold quality
rectum	UBERON:0001052	92.84	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.74	gold quality
body of stomach	UBERON:0001161	92.71	gold quality
granulocyte	CL:0000094	92.69	gold quality
sural nerve	UBERON:0015488	92.65	gold quality
adrenal tissue	UBERON:0018303	92.50	gold quality
left uterine tube	UBERON:0001303	92.46	gold quality
transverse colon	UBERON:0001157	92.42	gold quality
small intestine	UBERON:0002108	92.19	gold quality
body of uterus	UBERON:0009853	92.13	gold quality
body of pancreas	UBERON:0001150	92.02	gold quality
stomach	UBERON:0000945	92.00	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.87	gold quality
lower esophagus	UBERON:0013473	91.84	gold quality
endocervix	UBERON:0000458	91.80	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.80	gold quality
endometrium epithelium	UBERON:0004811	91.74	gold quality
ovary	UBERON:0000992	91.57	gold quality
right coronary artery	UBERON:0001625	91.39	gold quality
ectocervix	UBERON:0012249	91.35	gold quality
nerve	UBERON:0001021	91.27	gold quality
right uterine tube	UBERON:0001302	91.27	gold quality
tibial nerve	UBERON:0001323	91.27	gold quality
right lung	UBERON:0002167	91.18	gold quality
esophagus	UBERON:0001043	91.17	gold quality
vermiform appendix	UBERON:0001154	91.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	5.38

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

151 targeting KHNYN, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-1184	99.99	68.19	1458
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4487	99.96	64.58	1252
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-22-3P	99.93	68.13	917

Literature-anchored findings (GeneRIF, showing 2)

• KHNYN as a novel cofactor for ZAP to target CpG-containing retroviral RNA for degradation. (PMID:31284899)
• Crystallization and biochemical studies of the NYN domain of human KHNYN. (PMID:38376822)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Khnyn	ENSMUSG00000047153
rattus_norvegicus	Khnyn	ENSRNOG00000020506
drosophila_melanogaster	Regnase-1	FBGN0038769
drosophila_melanogaster	CG42360	FBGN0259742
caenorhabditis_elegans		WBGENE00013107
caenorhabditis_elegans	rege-1	WBGENE00016260
caenorhabditis_elegans		WBGENE00021287
caenorhabditis_elegans		WBGENE00021998
caenorhabditis_elegans		WBGENE00022003

Paralogs (6): ZC3H12B (ENSG00000102053), N4BP1 (ENSG00000102921), ZC3H12C (ENSG00000149289), ZC3H12A (ENSG00000163874), ZC3H12D (ENSG00000178199), NYNRIN (ENSG00000205978)

Protein

Protein identifiers

Protein KHNYN — O15037 (reviewed: O15037)

Alternative names: KH and NYN domain-containing protein

All UniProt accessions (3): O15037, G3V331, G3V3G3

UniProt curated annotations — full annotation on UniProt →

Similarity. Belongs to the N4BP1 family.

RefSeq proteins (3): NP_001277185, NP_001277186, NP_056114* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021869	RNase_Zc3h12_NYN	Domain
IPR036612	KH_dom_type_1_sf	Homologous_superfamily
IPR051101	ZC3H12/N4BP1_RNase_Reg	Family
IPR056578	UBA_N4BP1_C	Domain
IPR056629	KH_N4BP1_1st	Domain
IPR056630	KH_N4BP1_2nd	Domain

Pfam: PF11977, PF23050, PF23052, PF23054

UniProt features (33 total): helix 14, strand 6, region of interest 3, compositionally biased region 3, sequence variant 2, modified residue 2, chain 1, domain 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8WZC	X-RAY DIFFRACTION	1.93
9HTS	X-RAY DIFFRACTION	2.2
9BGL	X-RAY DIFFRACTION	2.29
9S2D	X-RAY DIFFRACTION	2.35
9CS9	X-RAY DIFFRACTION	2.5
2N5M	SOLUTION NMR
2N7K	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15037-F1	69.12	0.35

Functional residue map

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

Post-translational modifications (2): 10, 359

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 159 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, MORF_RAGE, AGGAAGC_MIR5163P, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, chr14q12, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, TTGGAGA_MIR5155P_MIR519E

GO Biological Process (1): biological_process (GO:0008150)

GO Molecular Function (5): mRNA binding (GO:0003729), RNA endonuclease activity (GO:0004521), molecular_function (GO:0003674), RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasmic ribonucleoprotein granule (GO:0036464), cellular_component (GO:0005575)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA binding	1
endonuclease activity	1
RNA nuclease activity	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
ribonucleoprotein granule	1

Protein interactions and networks

STRING

602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KHNYN	TRIM25	Q14258	718
KHNYN	ZC3HAV1	Q7Z2W4	717
KHNYN	RNASEL	Q05823	502
KHNYN	UNKL	Q9H9P5	463
KHNYN	ADGRA3	Q8IWK6	449
KHNYN	TNFRSF10D	Q9UBN6	420
KHNYN	SDR39U1	Q9NRG7	413
KHNYN	FAM171A1	Q5VUB5	393
KHNYN	OAS3	Q9Y6K5	389
KHNYN	XRN1	Q8IZH2	389
KHNYN	GBP5	Q96PP8	389
KHNYN	PARP12	Q9H0J9	366
KHNYN	CAMKK1	Q8N5S9	364
KHNYN	MARCHF1	Q8TCQ1	356
KHNYN	CERK	Q8TCT0	353
KHNYN	KDM6B	O15054	353

IntAct

46 interactions, top by confidence:

A	B	Type	Score
NEDD8	KHNYN	psi-mi:“MI:0915”(physical association)	0.700
KHNYN	NEDD8	psi-mi:“MI:0915”(physical association)	0.700
KHNYN	NEDD8	psi-mi:“MI:0407”(direct interaction)	0.700
OPG200	IKBKB	psi-mi:“MI:0914”(association)	0.620
KHNYN		psi-mi:“MI:0915”(physical association)	0.580
KHNYN		psi-mi:“MI:0914”(association)	0.580
KHNYN	RNF216	psi-mi:“MI:0915”(physical association)	0.560
KHNYN	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
KHNYN	PLOD3	psi-mi:“MI:0915”(physical association)	0.560
TKT	POTEF	psi-mi:“MI:0914”(association)	0.530
ZC3HAV1	KHNYN	psi-mi:“MI:0914”(association)	0.530
KHNYN	ENTREP1	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
RBCK1	UMAD1	psi-mi:“MI:0914”(association)	0.350
RBCK1	KHNYN	psi-mi:“MI:0914”(association)	0.350

BioGRID (42): KHNYN (Affinity Capture-MS), KHNYN (Affinity Capture-MS), KHNYN (Affinity Capture-MS), KHNYN (Affinity Capture-MS), KHNYN (Affinity Capture-MS), KHNYN (Protein-peptide), KHNYN (Protein-peptide), KHNYN (Reconstituted Complex), KHNYN (Reconstituted Complex), NEDD8 (Reconstituted Complex), UBC (Reconstituted Complex), NEDD8 (Affinity Capture-Western), CUL1 (Reconstituted Complex), CUL2 (Reconstituted Complex), NEDD8 (Co-crystal Structure)

ESM2 similar proteins: A0JPN4, A2A288, A2ARK0, A6ND36, A6QQJ8, A7E316, E9Q0S6, E9Q2Z1, O15037, O54714, O54967, O70260, O70405, O75385, O94983, P42335, P48778, Q07912, Q0P4K8, Q17R13, Q1LVK9, Q32PJ7, Q4V8I3, Q5D1E7, Q5D1E8, Q5DTV4, Q5HYM0, Q5JV73, Q5SWY7, Q5SXM2, Q5U2X5, Q5XIS1, Q68CZ2, Q6A037, Q6IRU7, Q6P1H6, Q6S5L8, Q7TP65, Q7TSG2, Q80U38

Diamond homologs: A0JPN4, A2A288, A6QQJ8, O15037, O75113, Q1LVK9, Q5D1E7, Q5D1E8, Q5DTV4, Q5DTZ0, Q5HYM0, Q5ZLE9, Q6A037, Q6DJS0, Q7ZXG4, Q80U38, Q8BIY3, Q95YE2, Q9C0D7, Q9P2P1, A6NKG5, Q8I7P9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical NF-kappaB signal transduction	5	13.0×	7e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	5	9.3×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	139
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2762 predictions. Top by Δscore:

Variant	Effect	Δscore
14:24428284:AC:A	donor_loss	1.0000
14:24428285:C:G	donor_loss	1.0000
14:24428307:CACCT:C	donor_gain	1.0000
14:24430927:CCAAG:C	donor_loss	1.0000
14:24430928:CAAG:C	donor_loss	1.0000
14:24430929:AAGG:A	donor_loss	1.0000
14:24430930:AGGT:A	donor_loss	1.0000
14:24430931:GGTGA:G	donor_loss	1.0000
14:24430932:G:GA	donor_loss	1.0000
14:24430933:T:G	donor_loss	1.0000
14:24432607:TGGT:T	donor_gain	1.0000
14:24432608:GGTG:G	donor_gain	1.0000
14:24432609:GT:G	donor_gain	1.0000
14:24432611:G:GG	donor_gain	1.0000
14:24432931:A:AG	acceptor_gain	1.0000
14:24432934:A:AG	acceptor_gain	1.0000
14:24432935:G:GG	acceptor_gain	1.0000
14:24432935:GAGA:G	acceptor_gain	1.0000
14:24436048:C:A	acceptor_gain	1.0000
14:24436055:T:A	acceptor_gain	1.0000
14:24436057:T:TA	acceptor_gain	1.0000
14:24436058:G:A	acceptor_gain	1.0000
14:24436063:T:TA	acceptor_gain	1.0000
14:24436175:GAACG:G	donor_gain	1.0000
14:24436386:A:AG	acceptor_gain	1.0000
14:24436387:G:GA	acceptor_gain	1.0000
14:24436387:GCC:G	acceptor_gain	1.0000
14:24436387:GCCT:G	acceptor_gain	1.0000
14:24436485:GCCAG:G	donor_gain	1.0000
14:24436486:CCAGG:C	donor_loss	1.0000

AlphaMissense

4393 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:24436113:T:A	V540D	1.000
14:24432589:A:T	D443V	0.999
14:24432808:T:A	V479D	0.999
14:24436089:C:A	A532D	0.999
14:24436116:C:T	S541F	0.999
14:24436122:A:T	D543V	0.999
14:24436420:T:C	F573S	0.999
14:24432583:T:A	V441D	0.998
14:24432586:T:A	I442N	0.998
14:24432592:G:A	G444D	0.998
14:24432594:A:C	S445R	0.998
14:24432596:C:A	S445R	0.998
14:24432596:C:G	S445R	0.998
14:24432780:T:A	W470R	0.998
14:24432780:T:C	W470R	0.998
14:24433026:A:T	D524V	0.998
14:24433029:A:C	D525A	0.998
14:24433029:A:T	D525V	0.998
14:24436103:G:T	G537W	0.998
14:24436104:G:A	G537E	0.998
14:24436116:C:A	S541Y	0.998
14:24436122:A:C	D543A	0.998
14:24436128:T:C	F545S	0.998
14:24436393:T:C	L564P	0.998
14:24437173:T:C	L642P	0.998
14:24432589:A:C	D443A	0.997
14:24432590:C:A	D443E	0.997
14:24432590:C:G	D443E	0.997
14:24432753:G:C	G461R	0.997
14:24432760:C:A	A463D	0.997

dbSNP variants (sampled 300 via entrez): RS1000260818 (14:24439000 G>A), RS1000300505 (14:24428239 C>T), RS1000399866 (14:24421735 G>A), RS1000564660 (14:24426607 C>A,T), RS1000598011 (14:24437137 G>A), RS1000999348 (14:24439052 T>C,G), RS1001311315 (14:24421470 T>C,G), RS1001346952 (14:24439385 C>T), RS1001403246 (14:24423128 T>A), RS1001407779 (14:24433178 A>AT), RS1001776218 (14:24439794 A>C,G), RS1001963359 (14:24434045 G>A,T), RS1002078356 (14:24435137 G>T), RS1002114493 (14:24437852 T>C), RS1002558024 (14:24441206 T>A)

Disease associations

OMIM: gene MIM:619579 | 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
GCST000759_4	LDL cholesterol	4.000000e-11
GCST90000025_531	Appendicular lean mass	8.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	3
Valproic Acid	affects expression, decreases expression	3
Tetrachlorodibenzodioxin	increases expression	2
FR900359	increases phosphorylation	1
malachite green	affects response to substance	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, increases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Atrazine	increases expression	1
Benzene	increases expression	1
Carbamazepine	affects expression	1
Manganese	increases abundance, increases expression	1
Mercuric Chloride	increases expression	1
Niclosamide	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Quercetin	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1
tert-Butylhydroperoxide	increases expression	1

Clinical trials (associated diseases)

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