DPH6

Summary

DPH6 (diphthamine biosynthesis 6, HGNC:30543) is a protein-coding gene on chromosome 15q14, encoding Diphthine–ammonia ligase (Q7L8W6). Amidase that may catalyze the last step of diphthamide biosynthesis using ammonium and ATP. It is a selective cancer dependency (DepMap: 29.2% of cell lines).

Enables diphthine-ammonia ligase activity. Predicted to be involved in protein histidyl modification to diphthamide. Predicted to be located in cytosol.

Source: NCBI Gene 89978 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 47 total
• Cancer dependency (DepMap): dependent in 29.2% of screened cell lines
• MANE Select transcript: NM_080650

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30543
Approved symbol	DPH6
Name	diphthamine biosynthesis 6
Location	15q14
Locus type	gene with protein product
Status	Approved
Aliases	MGC14798
Ensembl gene	ENSG00000134146
Ensembl biotype	protein_coding
OMIM	618391
Entrez	89978

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000256538, ENST00000440392, ENST00000558266, ENST00000558973, ENST00000559585, ENST00000559784, ENST00000560386, ENST00000560526, ENST00000561411, ENST00000896513

RefSeq mRNA: 2 — MANE Select: NM_080650 NM_001141972, NM_080650

CCDS: CCDS10043, CCDS45213

Canonical transcript exons

ENST00000256538 — 9 exons

Exon	Start	End
ENSE00000941739	35450685	35450803
ENSE00001172535	35370880	35372203
ENSE00001810547	35546119	35546165
ENSE00003516683	35410835	35410896
ENSE00003521726	35542413	35542507
ENSE00003522247	35373521	35373608
ENSE00003579597	35538274	35538467
ENSE00003600244	35454747	35454820
ENSE00003603112	35381822	35381916

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 90.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.2706 / max 312.3113, expressed in 1777 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149317	12.2706	1777

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	90.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.03	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.86	gold quality
adrenal tissue	UBERON:0018303	88.74	gold quality
muscle of leg	UBERON:0001383	87.16	gold quality
gastrocnemius	UBERON:0001388	87.12	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.44	gold quality
tibial artery	UBERON:0007610	84.38	gold quality
popliteal artery	UBERON:0002250	84.37	gold quality
tendon	UBERON:0000043	83.97	gold quality
tibialis anterior	UBERON:0001385	83.71	silver quality
ventricular zone	UBERON:0003053	83.64	gold quality
islet of Langerhans	UBERON:0000006	83.55	gold quality
body of pancreas	UBERON:0001150	82.66	gold quality
bone marrow cell	CL:0002092	82.43	gold quality
aorta	UBERON:0000947	82.25	gold quality
pancreas	UBERON:0001264	82.17	gold quality
left ovary	UBERON:0002119	81.80	gold quality
right ovary	UBERON:0002118	81.42	gold quality
skin of leg	UBERON:0001511	81.40	gold quality
esophagus mucosa	UBERON:0002469	81.38	gold quality
oocyte	CL:0000023	81.29	gold quality
skin of abdomen	UBERON:0001416	81.22	gold quality
secondary oocyte	CL:0000655	81.10	gold quality
mucosa of stomach	UBERON:0001199	80.86	gold quality
colonic epithelium	UBERON:0000397	80.80	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.62	gold quality
body of uterus	UBERON:0009853	80.49	gold quality
sural nerve	UBERON:0015488	80.44	gold quality
monocyte	CL:0000576	80.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting DPH6, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-369-3P	99.85	70.52	2264

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 29.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• The previously uncharacterized human gene ATPBD4 is the ortholog of yeast YLR143W, a diphthamide synthetase, and fully rescues the deletion of YLR143W in yeast. (PMID:23169644)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dph6	ENSDARG00000042839
mus_musculus	Dph6	ENSMUSG00000057147
rattus_norvegicus	Dph6	ENSRNOG00000037356
drosophila_melanogaster	CG1578	FBGN0030336
caenorhabditis_elegans	dph-6	WBGENE00017087

Protein

Protein identifiers

Diphthine–ammonia ligase — Q7L8W6 (reviewed: Q7L8W6)

Alternative names: ATP-binding domain-containing protein 4, Diphthamide synthase, Diphthamide synthetase, Protein DPH6 homolog

All UniProt accessions (3): Q7L8W6, H0YND7, H0YNH5

UniProt curated annotations — full annotation on UniProt →

Function. Amidase that may catalyze the last step of diphthamide biosynthesis using ammonium and ATP. Diphthamide biosynthesis consists in the conversion of an L-histidine residue in the translation elongation factor (EEF2) to diphthamide.

Pathway. Protein modification; peptidyl-diphthamide biosynthesis.

Miscellaneous. When transfected in S.cerevisiae, able to restore diphthamide biosynthesis in a strain lacking DPH6.

Similarity. Belongs to the Diphthine–ammonia ligase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q7L8W6-1	1	yes
Q7L8W6-2	2

RefSeq proteins (2): NP_001135444, NP_542381* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002761	Diphthami_syn_dom	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR030662	DPH6/MJ0570	Family

Pfam: PF01902

Catalyzed reactions (Rhea), 1 shown:

• diphthine-[translation elongation factor 2] + NH4(+) + ATP = diphthamide-[translation elongation factor 2] + AMP + diphosphate + H(+) (RHEA:19753)

UniProt features (5 total): sequence variant 2, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7L8W6-F1	89.85	0.78

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 (1): 97

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5358493	Synthesis of diphthamide-EEF2

MSigDB gene sets: 124 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, chr15q14, INGRAM_SHH_TARGETS_UP, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_NITROGEN_BONDS, BENPORATH_NOS_TARGETS, NUYTTEN_EZH2_TARGETS_DN, BENPORATH_OCT4_TARGETS, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, WANG_TUMOR_INVASIVENESS_DN, GOMF_ADENYL_NUCLEOTIDE_BINDING, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PEPTIDYL_HISTIDINE_MODIFICATION, RAO_BOUND_BY_SALL4_ISOFORM_B

GO Biological Process (1): protein histidyl modification to diphthamide (GO:0017183)

GO Molecular Function (4): ATP binding (GO:0005524), diphthine-ammonia ligase activity (GO:0017178), nucleotide binding (GO:0000166), ligase activity (GO:0016874)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidyl-histidine modification	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
acid-ammonia (or amide) ligase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPH6	DPH7	Q9BTV6	853
DPH6	DPH5	Q9H2P9	839
DPH6	DPH2	Q9BQC3	815
DPH6	DPH3	Q96FX2	811
DPH6	DPH1	Q9BZG8	810
DPH6	DNAJC24	Q6P3W2	747
DPH6	EEF2	P13639	522
DPH6	RIDA	P52758	499
DPH6	ELP5	Q8TE02	494
DPH6	CDIN1	Q9Y2V0	471
DPH6	PPP1R1C	Q8WVI7	459
DPH6	GBE1	Q04446	458
DPH6	ABHD17A	Q96GS6	445
DPH6	CFAP20DC	Q6ZVT6	436
DPH6	PARP4	Q9UKK3	433

IntAct

29 interactions, top by confidence:

A	B	Type	Score
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
CT55	DPH6	psi-mi:“MI:0915”(physical association)	0.400
DPH6	SMARCB1	psi-mi:“MI:0915”(physical association)	0.370
C5AR2	ILVBL	psi-mi:“MI:0914”(association)	0.350
TMCO3	POTEF	psi-mi:“MI:0914”(association)	0.350
SLC18A1	LIMK2	psi-mi:“MI:0914”(association)	0.350
GRPR	GPR89A	psi-mi:“MI:0914”(association)	0.350
PTGIR	GPAA1	psi-mi:“MI:0914”(association)	0.350
DPH6	ATP2B2	psi-mi:“MI:0914”(association)	0.350
S100A8	SMTNL2	psi-mi:“MI:0914”(association)	0.350
S100A6	VWA8	psi-mi:“MI:0914”(association)	0.350
CD80	POTEF	psi-mi:“MI:0914”(association)	0.350
C5AR1	TCAF2	psi-mi:“MI:0914”(association)	0.350
B3GAT1	RTL8C	psi-mi:“MI:0914”(association)	0.350
FPR1	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC18A1	UBXN8	psi-mi:“MI:0914”(association)	0.350
ADAMTS4	RAD51B	psi-mi:“MI:0914”(association)	0.350
CD80	RIMOC1	psi-mi:“MI:0914”(association)	0.350
CXCR3	RIMOC1	psi-mi:“MI:0914”(association)	0.350
DPH6	ERBB2	psi-mi:“MI:0914”(association)	0.350
EFNB2	TCAF2	psi-mi:“MI:0914”(association)	0.350
GPR17	C1QTNF9B	psi-mi:“MI:0914”(association)	0.350
HS2ST1	CLGN	psi-mi:“MI:0914”(association)	0.350
SRPRB	GSDME	psi-mi:“MI:0914”(association)	0.350
SSTR2	PJA2	psi-mi:“MI:0914”(association)	0.350

BioGRID (40): ATP2B2 (Affinity Capture-MS), KIAA1919 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), ATP2B2 (Affinity Capture-MS), KIAA1919 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), DPH6 (Two-hybrid), DPH6 (Positive Genetic), DPH6 (Affinity Capture-MS), DPH6 (Positive Genetic)

ESM2 similar proteins: A1K983, A2RV01, A4G213, A4ILN7, A4VN94, A5F2F2, A6SUW6, A7MFJ8, A9BS40, B0TQ02, B1JD61, B1YFM6, B2I4Y4, B3PC22, B5FG83, B7GLA4, B7UXV6, C3JYR8, C5D7Y2, Q02ID8, Q0ADM9, Q0VRI8, Q12FK2, Q1GZF5, Q21HP4, Q21K42, Q2HJF5, Q2SJL8, Q2Y6T6, Q31H76, Q3IH16, Q47AW0, Q5L1C0, Q5LFI6, Q5M9F5, Q5P7R7, Q5WG41, Q609K0, Q64WB0, Q6LT18

Diamond homologs: A2RV01, Q12429, Q2HJF5, Q57990, Q5M9F5, Q7L8W6, Q9CQ28, Q9USQ7, O25598, P40037, P52758, P52760, Q94JQ4, Q9ZKQ6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 40 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 cytosolic calcium ion concentration	5	17.7×	1e-03
inflammatory response	7	8.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3138 predictions. Top by Δscore:

Variant	Effect	Δscore
15:35381820:A:AC	donor_gain	1.0000
15:35381821:C:CC	donor_gain	1.0000
15:35381821:CA:C	donor_gain	1.0000
15:35381873:TCTC:T	donor_gain	1.0000
15:35381874:CTCC:C	donor_gain	1.0000
15:35381912:GAAAG:G	acceptor_gain	1.0000
15:35381917:C:CC	acceptor_gain	1.0000
15:35429860:G:C	donor_gain	1.0000
15:35450662:C:CA	donor_gain	1.0000
15:35454745:A:AC	donor_gain	1.0000
15:35454746:C:CC	donor_gain	1.0000
15:35454746:CA:C	donor_gain	1.0000
15:35454746:CACA:C	donor_gain	1.0000
15:35455812:C:CT	donor_gain	1.0000
15:35455813:T:TT	donor_gain	1.0000
15:35538269:CATA:C	donor_loss	1.0000
15:35538270:ATAC:A	donor_loss	1.0000
15:35538271:TA:T	donor_loss	1.0000
15:35538272:A:AT	donor_loss	1.0000
15:35538273:CCTT:C	donor_loss	1.0000
15:35538305:TCA:T	donor_gain	1.0000
15:35538463:CCCCA:C	acceptor_gain	1.0000
15:35538464:CCCA:C	acceptor_gain	1.0000
15:35538464:CCCAC:C	acceptor_gain	1.0000
15:35538465:CCA:C	acceptor_gain	1.0000
15:35538465:CCAC:C	acceptor_gain	1.0000
15:35538466:CA:C	acceptor_gain	1.0000
15:35538466:CAC:C	acceptor_gain	1.0000
15:35538467:AC:A	acceptor_loss	1.0000
15:35538468:C:CC	acceptor_gain	1.0000

AlphaMissense

1748 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:35450699:T:A	K164I	0.997
15:35454767:C:A	Q122H	0.997
15:35454767:C:G	Q122H	0.997
15:35454783:A:T	I117K	0.997
15:35542497:C:G	D12H	0.997
15:35381850:A:G	C212R	0.996
15:35542492:G:C	S13R	0.996
15:35542492:G:T	S13R	0.996
15:35542494:T:G	S13R	0.996
15:35542495:G:C	D12E	0.996
15:35542495:G:T	D12E	0.996
15:35542496:T:G	D12A	0.996
15:35542498:C:A	K11N	0.996
15:35542498:C:G	K11N	0.996
15:35381867:T:A	E206V	0.995
15:35381882:T:A	E201V	0.995
15:35381887:A:C	C199W	0.995
15:35450698:T:A	K164N	0.995
15:35450698:T:G	K164N	0.995
15:35450766:A:G	W142R	0.995
15:35450766:A:T	W142R	0.995
15:35538445:G:C	S47R	0.995
15:35538445:G:T	S47R	0.995
15:35538447:T:G	S47R	0.995
15:35542471:G:C	C20W	0.995
15:35542496:T:A	D12V	0.995
15:35381888:C:T	C199Y	0.994
15:35381889:A:G	C199R	0.994
15:35450800:A:C	C130W	0.994
15:35454759:C:G	R125P	0.994

dbSNP variants (sampled 300 via entrez): RS1000004401 (15:35283750 C>T), RS1000008461 (15:35343901 T>C), RS1000010502 (15:35255298 C>G), RS1000012488 (15:35512752 T>C), RS1000016782 (15:35194509 T>C), RS1000017630 (15:35476309 G>T), RS1000020017 (15:35507022 T>C), RS1000027566 (15:35446688 A>G), RS1000031057 (15:35211306 A>G), RS1000036343 (15:35303319 T>C), RS1000046174 (15:35460565 C>T), RS1000048122 (15:35194210 T>C), RS1000050300 (15:35177613 A>C,G), RS1000051449 (15:35247204 C>G), RS1000063261 (15:35381576 C>A,T)

Disease associations

OMIM: gene MIM:618391 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000684_7	Attention deficit hyperactivity disorder	2.000000e-06
GCST002074_9	Paclitaxel-induced neuropathy	4.000000e-06
GCST002192_2	Menopause (age at onset)	5.000000e-06
GCST003059_19	Parkinson’s disease	1.000000e-06
GCST003992_40	Photic sneeze reflex	6.000000e-17
GCST004047_3	Optic nerve measurement (cup-to-disc ratio)	1.000000e-06
GCST005042_14	Restless legs syndrome	3.000000e-27
GCST010396_191	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-06
GCST012047_10	Fasting glucose	5.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0006939	cup-to-disc ratio measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	4
Cyclosporine	increases expression	3
sodium arsenite	decreases expression, affects expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases methylation	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	decreases expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Irinotecan	decreases expression	1
Temozolomide	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Ethyl Methanesulfonate	decreases expression	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Quercetin	decreases expression	1

Clinical trials (associated diseases)

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