SRP54

Summary

SRP54 (signal recognition particle 54, HGNC:11301) is a protein-coding gene on chromosome 14q13.2, encoding Signal recognition particle subunit SRP54 (P61011). Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

Enables several functions, including 7S RNA binding activity; endoplasmic reticulum signal peptide binding activity; and guanyl ribonucleotide binding activity. Contributes to GTPase activity. Involved in granulocyte differentiation and protein targeting to ER. Located in cytosol and nucleus. Part of signal recognition particle, endoplasmic reticulum targeting. Implicated in severe congenital neutropenia 8.

Source: NCBI Gene 6729 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neutropenia, severe congenital, 8, autosomal dominant (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 358 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 43
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_003136

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11301
Approved symbol	SRP54
Name	signal recognition particle 54
Location	14q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100883
Ensembl biotype	protein_coding
OMIM	604857
Entrez	6729

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 20 protein_coding, 8 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000216774, ENST00000546080, ENST00000553544, ENST00000553923, ENST00000554803, ENST00000555317, ENST00000555535, ENST00000555557, ENST00000555746, ENST00000556380, ENST00000556445, ENST00000556992, ENST00000556994, ENST00000677561, ENST00000677621, ENST00000677647, ENST00000678274, ENST00000678477, ENST00000678519, ENST00000678627, ENST00000678836, ENST00000678963, ENST00000679045, ENST00000859403, ENST00000859404, ENST00000859405, ENST00000928722, ENST00000928723, ENST00000928724, ENST00000928725, ENST00000928726, ENST00000968000, ENST00000968001, ENST00000968002

RefSeq mRNA: 3 — MANE Select: NM_003136 NM_001146282, NM_001411017, NM_003136

CCDS: CCDS91863, CCDS9652

Canonical transcript exons

ENST00000216774 — 16 exons

Exon	Start	End
ENSE00002430174	34982992	34983215
ENSE00003481166	34999558	34999649
ENSE00003509374	35000936	35001020
ENSE00003540376	35018692	35018765
ENSE00003687630	35011509	35011659
ENSE00003889047	35028088	35028183
ENSE00003889518	35013802	35013902
ENSE00003890148	35018966	35019074
ENSE00003890735	35013346	35013494
ENSE00003890937	35007283	35007387
ENSE00003890998	35008774	35008831
ENSE00003891480	35029061	35029567
ENSE00003892339	35014744	35014830
ENSE00003892990	35022910	35023080
ENSE00003895033	35008627	35008693
ENSE00003906262	34996677	34996787

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 97.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.9587 / max 952.8712, expressed in 1819 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139193	46.7815	1818
139191	4.2953	1349
139195	3.5168	1241
139194	3.1163	1400
139192	1.2395	798
139196	0.0094	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	97.51	gold quality
pancreas	UBERON:0001264	96.54	gold quality
islet of Langerhans	UBERON:0000006	96.47	gold quality
sperm	CL:0000019	96.37	gold quality
calcaneal tendon	UBERON:0003701	96.25	gold quality
right testis	UBERON:0004534	95.75	gold quality
cartilage tissue	UBERON:0002418	95.62	gold quality
adenohypophysis	UBERON:0002196	95.60	gold quality
left testis	UBERON:0004533	95.55	gold quality
right lobe of liver	UBERON:0001114	95.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.23	gold quality
stromal cell of endometrium	CL:0002255	95.23	gold quality
minor salivary gland	UBERON:0001830	94.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.94	gold quality
pituitary gland	UBERON:0000007	94.94	gold quality
testis	UBERON:0000473	94.94	gold quality
saliva-secreting gland	UBERON:0001044	94.75	gold quality
adrenal tissue	UBERON:0018303	94.55	gold quality
male germ cell	CL:0000015	94.40	gold quality
mouth mucosa	UBERON:0003729	94.26	gold quality
rectum	UBERON:0001052	94.20	gold quality
tonsil	UBERON:0002372	94.01	gold quality
mucosa of stomach	UBERON:0001199	93.85	gold quality
right adrenal gland	UBERON:0001233	93.75	gold quality
body of stomach	UBERON:0001161	93.72	gold quality
descending thoracic aorta	UBERON:0002345	93.72	gold quality
monocyte	CL:0000576	93.68	gold quality
skin of abdomen	UBERON:0001416	93.64	gold quality
left adrenal gland	UBERON:0001234	93.59	gold quality
right adrenal gland cortex	UBERON:0035827	93.57	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	604.11
E-MTAB-4850	no	710.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

58 targeting SRP54, 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-4533	100.00	69.48	2758
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 9)

• crystal structure of a human SRP ternary complex consisting of SRP19, the M domain of SRP54 and the S domain of 7SL RNA (PMID:12244299)
• autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype. (PMID:28972538)
• This study identified SRP54 mutations in congenital neutropenia. SRP54 mutations induce endoplasmic reticulum stress and autophagy associated with apoptosis. (PMID:29914977)
• Whole exome sequencing discloses heterozygous variants in the DNAJC21 and EFL1 genes but not in SRP54 in 6 out of 16 patients with Shwachman-Diamond Syndrome carrying biallelic SBDS mutations. (PMID:30198570)
• e show that SRP RNA does not bind to the ribosome, while SRP binds with nanomolar affinity involving a two-step mechanism of the key-player SRP54. Ultrasensitive binding of SRP68/72 indicates avidity by multiple binding sites that are dominated by the C-terminus of SRP72 (PMID:30649417)
• Congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene. (PMID:32277798)
• Structural and Functional Impact of SRP54 Mutations Causing Severe Congenital Neutropenia. (PMID:33053321)
• SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing. (PMID:33227812)
• Autosomal dominant Shwachman-Diamond syndrome with a novel heterozygous missense variant in the SRP54 gene causing severe phenotypic features. (PMID:34549814)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	srp54	ENSDARG00000098367
mus_musculus	Srp54a	ENSMUSG00000073079
mus_musculus	Srp54c	ENSMUSG00000079108
mus_musculus	Srp54b	ENSMUSG00000112449
rattus_norvegicus	Srp54a	ENSRNOG00000032776
drosophila_melanogaster	Srp54k	FBGN0010747
caenorhabditis_elegans		WBGENE00009012

Paralogs (1): SRPRA (ENSG00000182934)

Protein

Protein identifiers

Signal recognition particle subunit SRP54 — P61011 (reviewed: P61011)

Alternative names: Signal recognition particle 54 kDa protein

All UniProt accessions (10): P61011, A0A7I2V584, A0A7I2V591, A0A7I2V5K0, A0A7I2V5S0, A0A7P0PJI2, G3V346, G3V3L9, G3V480, G3V4F7

UniProt curated annotations — full annotation on UniProt →

Function. Component of the signal recognition particle (SRP) complex, a ribonucleoprotein complex that mediates the cotranslational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). As part of the SRP complex, associates with the SRP receptor (SR) component SRPRA to target secretory proteins to the endoplasmic reticulum membrane. Binds to the signal sequence of presecretory proteins when they emerge from the ribosomes. Displays basal GTPase activity, and stimulates reciprocal GTPase activation of the SR subunit SRPRA. Forms a guanosine 5’-triphosphate (GTP)-dependent complex with the SR subunit SRPRA. SR compaction and GTPase mediated rearrangement of SR drive SRP-mediated cotranslational protein translocation into the ER. Requires the presence of SRP9/SRP14 and/or SRP19 to stably interact with RNA. Plays a role in proliferation and differentiation of granulocytic cells, neutrophils migration capacity and exocrine pancreas development.

Subunit / interactions. Component of a signal recognition particle (SRP) complex that consists of a 7SL RNA molecule of 300 nucleotides and six protein subunits: SRP72, SRP68, SRP54, SRP19, SRP14 and SRP9. Interacts with RNPS1. Interacts with the SRP receptor subunit SRPRA.

Subcellular location. Nucleus speckle. Cytoplasm. Endoplasmic reticulum.

Disease relevance. Neutropenia, severe congenital 8, autosomal dominant (SCN8) [MIM:618752] A form of severe congenital neutropenia, a disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The NG domain, also named G domain, is a special guanosine triphosphatase (GTPase) domain, which binds GTP and forms a guanosine 5’-triphosphate (GTP)-dependent complex with a homologous NG domain in the SRP receptor subunit SRPRA. The two NG domains undergo cooperative rearrangements upon their assembly, which culminate in the reciprocal activation of the GTPase activity of one another. SRP receptor compaction upon binding with cargo-loaded SRP and GTPase rearrangement drive SRP-mediated cotranslational protein translocation into the ER. The M domain binds the 7SL RNA in presence of SRP19 and binds the signal sequence of presecretory proteins.

Similarity. Belongs to the GTP-binding SRP family. SRP54 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P61011-1	1	yes
P61011-2	2

RefSeq proteins (3): NP_001139754, NP_001397946, NP_003127* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000897	SRP54_GTPase_dom	Domain
IPR003593	AAA+_ATPase	Domain
IPR004125	Signal_recog_particle_SRP54_M	Domain
IPR006325	SRP54_euk	Family
IPR013822	Signal_recog_particl_SRP54_hlx	Domain
IPR022941	SRP54	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036225	SRP/SRP_N	Homologous_superfamily
IPR036891	Signal_recog_part_SRP54_M_sf	Homologous_superfamily
IPR042101	SRP54_N_sf	Homologous_superfamily

Pfam: PF00448, PF02881, PF02978

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (48 total): helix 19, strand 10, sequence variant 8, turn 4, binding site 3, region of interest 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
1QB2	X-RAY DIFFRACTION	2.1
6Y2Z	X-RAY DIFFRACTION	2.15
6Y32	X-RAY DIFFRACTION	2.6
6Y30	X-RAY DIFFRACTION	2.65
7QWQ	ELECTRON MICROSCOPY	2.83
1MFQ	X-RAY DIFFRACTION	3.1
5L3Q	X-RAY DIFFRACTION	3.2
7NFX	ELECTRON MICROSCOPY	3.2
6Y31	X-RAY DIFFRACTION	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61011-F1	79.68	0.29

Functional residue map

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

Ligand- & substrate-binding residues (3): 108–115; 190–194; 248–251

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1799339	SRP-dependent cotranslational protein targeting to membrane
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 346 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, MODULE_149, CAGCTG_AP4_Q5, GOBP_PANCREAS_DEVELOPMENT, GOBP_LEUKOCYTE_CHEMOTAXIS, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, GOBP_TAXIS

GO Biological Process (7): SRP-dependent cotranslational protein targeting to membrane (GO:0006614), SRP-dependent cotranslational protein targeting to membrane, translocation (GO:0006616), SRP-dependent cotranslational protein targeting to membrane, signal sequence recognition (GO:0006617), neutrophil chemotaxis (GO:0030593), granulocyte differentiation (GO:0030851), exocrine pancreas development (GO:0031017), protein targeting to ER (GO:0045047)

GO Molecular Function (11): RNA binding (GO:0003723), GTPase activity (GO:0003924), GTP binding (GO:0005525), 7S RNA binding (GO:0008312), GDP binding (GO:0019003), endoplasmic reticulum signal sequence receptor activity (GO:0030942), ribonucleoprotein complex binding (GO:0043021), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), ATP hydrolysis activity (GO:0016887)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), signal recognition particle, endoplasmic reticulum targeting (GO:0005786), cytosol (GO:0005829), nuclear speck (GO:0016607), signal recognition particle (GO:0048500), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
SRP-dependent cotranslational protein targeting to membrane	2
ribonucleoside triphosphate phosphatase activity	2
guanyl ribonucleotide binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
translation	1
cotranslational protein targeting to membrane	1
protein targeting to ER	1
intracellular protein transmembrane transport	1
protein-containing complex assembly	1
granulocyte chemotaxis	1
neutrophil migration	1
myeloid leukocyte differentiation	1
pancreas development	1
exocrine system development	1
gland development	1
digestive system development	1
protein targeting	1
establishment of protein localization to endoplasmic reticulum	1
nucleic acid binding	1
purine ribonucleoside triphosphate binding	1
RNA binding	1
anion binding	1
signal sequence receptor activity	1
protein-containing complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
ATP-dependent activity	1
intracellular anatomical structure	1
endomembrane system	1
signal recognition particle	1
nuclear ribonucleoprotein granule	1
ribonucleoprotein complex	1
protein-containing complex	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

104 interactions, top by confidence:

A	B	Type	Score
HSPA8	GAK	psi-mi:“MI:0914”(association)	0.760
SRP9	SRP72	psi-mi:“MI:0914”(association)	0.730
SRP68	SRP72	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
rep	MPHOSPH10	psi-mi:“MI:0914”(association)	0.660
SRP14	PPM1G	psi-mi:“MI:0914”(association)	0.640
CFAP47	UBB	psi-mi:“MI:0914”(association)	0.560
SRP54	SRPRA	psi-mi:“MI:0407”(direct interaction)	0.560
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
SRP72	SRP19	psi-mi:“MI:0914”(association)	0.530
CPLX2	CPLX1	psi-mi:“MI:0914”(association)	0.530
SRP68	MAGEB2	psi-mi:“MI:0914”(association)	0.530
MAGEB2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
	AP3D1	psi-mi:“MI:0914”(association)	0.460
SRP54	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.400
STK4	EIF3CL	psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
Srp72		psi-mi:“MI:0914”(association)	0.350

BioGRID (195): SMC2 (Co-fractionation), SMC4 (Co-fractionation), SRP19 (Co-fractionation), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS), SRP54 (Affinity Capture-MS)

ESM2 similar proteins: A0B638, A2STI3, A4FVX4, A4YHL0, A5UMY7, A6UQJ8, A6UWG4, A6VHE0, A9A9B0, B6YSS1, O07853, O15821, O27376, O29633, O67615, P14576, P21565, P37106, P49966, P49967, P49968, P49969, P49970, P49971, P49972, P56005, P61010, P61011, P75054, Q01442, Q0W2G1, Q12ZG8, Q2NE47, Q2T9U1, Q46E01, Q4R965, Q54431, Q55311, Q57565, Q5JJC8

Diamond homologs: A0B638, A1RS43, A2BNB5, A2STI3, A3DML3, A3MWX6, A4FVX4, A4WLQ3, A4YHL0, A5UMY7, A6UQJ8, A6UWG4, A6VHE0, A9A9B0, B0R7X3, B1Y9L4, B6YSS1, B9LT33, C3MPN4, C3MYM8, C3N5B0, C3NDW4, C3NHT9, C4KGX6, C5A233, O07347, O07853, O15821, O27376, O29633, O33013, O42816, O59307, O67615, P0AGD7, P0AGD8, P0AGD9, P14576, P20424, P21565

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
SRP54	“up-regulates activity”	SRSF2	binding
SRP54	“up-regulates activity”	SRSF1	binding
SRP54	“up-regulates activity”	U2AF1/U2AF2	binding
SRP54	“up-regulates activity”	SRPRA	binding
SRP54	“up-regulates activity”	SRPRB	binding
SRP19	“up-regulates activity”	SRP54	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
SRP-dependent cotranslational protein targeting to membrane	15	17.3×	3e-12
Eukaryotic Translation Termination	10	13.8×	3e-07
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	10	13.5×	3e-07
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	10	13.5×	3e-07
Peptide chain elongation	9	13.1×	1e-06
Viral mRNA Translation	9	13.1×	1e-06
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	9	13.0×	1e-06
Response of EIF2AK4 (GCN2) to amino acid deficiency	10	12.7×	4e-07

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	10	17.5×	1e-07
translation	14	13.6×	2e-09
ribosomal small subunit biogenesis	6	12.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	138
Likely benign	161
Benign	36

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
430851	NM_003136.4(SRP54):c.343A>G (p.Thr115Ala)	Pathogenic
810689	NM_003136.4(SRP54):c.668C>A (p.Ala223Asp)	Pathogenic
810690	NM_003136.4(SRP54):c.821G>A (p.Gly274Asp)	Pathogenic
810688	NM_003136.4(SRP54):c.337G>C (p.Gly113Arg)	Likely pathogenic
985721	NM_003136.4(SRP54):c.331G>A (p.Gly111Arg)	Likely pathogenic

SpliceAI

2071 predictions. Top by Δscore:

Variant	Effect	Δscore
14:34996669:T:A	acceptor_gain	1.0000
14:34996672:T:A	acceptor_gain	1.0000
14:34996674:TA:T	acceptor_loss	1.0000
14:34996675:A:AG	acceptor_gain	1.0000
14:34996676:G:GC	acceptor_gain	1.0000
14:34996676:GA:G	acceptor_gain	1.0000
14:34996676:GAGT:G	acceptor_gain	1.0000
14:34996676:GAGTT:G	acceptor_gain	1.0000
14:34996783:AAGAG:A	donor_gain	1.0000
14:34996784:AGAG:A	donor_gain	1.0000
14:34996785:GAG:G	donor_gain	1.0000
14:34996785:GAGG:G	donor_gain	1.0000
14:34996786:AG:A	donor_gain	1.0000
14:34996786:AGGTA:A	donor_loss	1.0000
14:34996787:GG:G	donor_gain	1.0000
14:34996788:G:C	donor_loss	1.0000
14:34996788:G:GG	donor_gain	1.0000
14:34996789:T:A	donor_loss	1.0000
14:34999645:GTTAA:G	donor_gain	1.0000
14:34999646:T:G	donor_gain	1.0000
14:34999650:G:GG	donor_gain	1.0000
14:35000913:A:AG	acceptor_gain	1.0000
14:35007282:GCTT:G	acceptor_gain	1.0000
14:35008626:GCTA:G	acceptor_gain	1.0000
14:35008770:CCA:C	acceptor_loss	1.0000
14:35008771:CAG:C	acceptor_loss	1.0000
14:35008772:A:AG	acceptor_gain	1.0000
14:35008772:AG:A	acceptor_gain	1.0000
14:35008772:AGG:A	acceptor_gain	1.0000
14:35008772:AGGG:A	acceptor_gain	1.0000

AlphaMissense

3408 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:34999603:G:C	A42P	1.000
14:34999634:T:C	L52P	1.000
14:34999646:T:A	V56D	1.000
14:35001013:T:C	L83P	1.000
14:35007347:T:A	V107D	1.000
14:35007349:G:A	G108R	1.000
14:35007349:G:C	G108R	1.000
14:35007350:G:A	G108E	1.000
14:35007350:G:T	G108V	1.000
14:35007358:G:A	G111R	1.000
14:35007358:G:C	G111R	1.000
14:35007358:G:T	G111W	1.000
14:35007359:G:A	G111E	1.000
14:35007364:G:C	G113R	1.000
14:35007365:G:A	G113D	1.000
14:35007365:G:T	G113V	1.000
14:35007367:A:C	K114Q	1.000
14:35007368:A:T	K114I	1.000
14:35007369:A:C	K114N	1.000
14:35007369:A:T	K114N	1.000
14:35007371:C:T	T115I	1.000
14:35007381:T:G	C118W	1.000
14:35007385:A:G	K120E	1.000
14:35007387:G:C	K120N	1.000
14:35007387:G:T	K120N	1.000
14:35008631:C:A	A122E	1.000
14:35008670:T:A	I135K	1.000
14:35008672:T:C	C136R	1.000
14:35008673:G:A	C136Y	1.000
14:35008674:T:G	C136W	1.000

dbSNP variants (sampled 300 via entrez): RS1000021037 (14:35009937 C>G,T), RS1000021295 (14:35001271 C>T), RS1000385601 (14:34987829 C>A,T), RS1000461098 (14:34983563 A>C), RS1000513180 (14:34999945 T>C), RS1000555388 (14:34983403 C>A,T), RS1000564045 (14:35025167 T>C), RS1000588982 (14:34993470 A>C,T), RS1000737212 (14:34988189 T>A), RS1000744257 (14:35006137 C>T), RS1000797228 (14:35004895 C>T), RS1000835597 (14:34981912 C>T), RS1000875656 (14:34987676 A>G), RS1000934887 (14:35023991 A>G,T), RS1000940605 (14:34982281 T>A,C,G)

Disease associations

OMIM: gene MIM:604857 | disease phenotypes: MIM:618752, MIM:260400, MIM:618300

GenCC curated gene-disease

Disease	Classification	Inheritance
neutropenia, severe congenital, 8, autosomal dominant	Strong	Autosomal dominant
autosomal dominant severe congenital neutropenia	Supportive	Autosomal dominant
Shwachman-Diamond syndrome	Supportive	Autosomal recessive

Mondo (5): neutropenia, severe congenital, 8, autosomal dominant (MONDO:0032899), Shwachman-Diamond syndrome 1 (MONDO:0044204), ciliary dyskinesia, primary, 40 (MONDO:0032664), autosomal dominant severe congenital neutropenia (MONDO:0008742), Shwachman-Diamond syndrome (MONDO:0009833)

Orphanet (1): Severe congenital neutropenia-developmental delay syndrome due to SRP54 deficiency (Orphanet:675767)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000729	Autistic behavior
HP:0000774	Narrow chest
HP:0000907	Anterior rib cupping
HP:0000920	Enlargement of the costochondral junction
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001700	Myocardial necrosis
HP:0001738	Exocrine pancreatic insufficiency
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001903	Anemia
HP:0002098	Respiratory distress
HP:0002240	Hepatomegaly
HP:0002570	Steatorrhea
HP:0002643	Neonatal respiratory distress
HP:0002719	Recurrent infections
HP:0002750	Delayed skeletal maturation
HP:0002812	Coxa vara
HP:0002863	Myelodysplasia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003016	Metaphyseal widening
HP:0003300	Ovoid vertebral bodies
HP:0003375	Narrow greater sciatic notch

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004028_7	Immunoglobulin light chain (AL) amyloidosis	3.000000e-06
GCST006979_1043	Heel bone mineral density	4.000000e-12
GCST012227_585	Hip circumference adjusted for BMI	4.000000e-08
GCST90020026_234	Hip index	4.000000e-14
GCST90020028_1860	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295786 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases activity, increases expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
sodium arsenate	decreases expression	1
salinomycin	decreases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
pentabromodiphenyl ether	increases expression	1
K 7174	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Benzene	increases expression	1
Bile Acids and Salts	increases expression	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	increases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Ivermectin	decreases expression	1
Ketoconazole	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Polycyclic Aromatic Hydrocarbons	increases abundance, affects cotreatment, decreases expression	1
Ribonucleotides	affects binding	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119038	Binding	Binding affinity to SRP54 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT03333486	PHASE2	TERMINATED	Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00176852	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00176878	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Bone Marrow Failure Syndromes
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02011074	Not specified	COMPLETED	Perioperative Changes of Heart Rate Variability Related to Anxiety and Depressiveness in Patients Undergoing General Anesthesia
NCT02179359	Not specified	TERMINATED	Hematopoietic Stem Cell Transplant for High Risk Hemoglobinopathies
NCT04275479	Not specified	TERMINATED	Diabetes/ Endocrine Surveillance in SDS
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06056908	Not specified	RECRUITING	Shwachman Diamond Syndrome Registry and Study
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform