PPIP5K2

protein-coding

diphosphoinositol pentakisphosphate kinase 2, the group of Cilia and flagella associated

Gene summary

This gene encodes a member of the histidine acid phosphatase family of proteins. Despite containing a histidine acid phosphatase domain, the encoded protein functions as an inositol pyrophosphate kinase, and is thought to lack phosphatase activity. This kinase activity is the mechanism by which the encoded protein synthesizes high-energy inositol pyrophosphates, which act as signaling molecules that regulate cellular homeostasis and other processes. This gene may be associated with autism spectrum disorder in human patients. [provided by RefSeq, Sep 2016]

Previous symbols:

HISPPD1
DFNB100

MANE transcript

NM_001276277.3

Inheritance

ClinVar variants

P:1U:108B:17

Top phenotype

Deafness, autosomal recessive 100

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr5:103,120,149-103,212,799

External References & Databases

Ensembl (ENSG00000145725)

Transcript & Mutation Effects

hg38 • Region Span ~92.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: ClinGen

PPIP5K2 was first reported in relation to autosomal recessive nonsyndromic hearing loss in 2018 (Yousaf et al., PMID: 29590114). One missense variant (c.2510G>A, p.Arg837His) that has been reported in 12 affected individuals across two families in one publication (PMID: 29590114) is included in this curation. The affected individuals presented with prelingual bilateral severe to profound sensorineural hearing loss. This gene-disease relationship is also supported by expression data indicating that PPIP5K2 is expressed in the cochlear and vestibular sensory hair cells, supporting cells, and ganglion neurons. A mouse model also showed that PPIP5K2 with a truncated phosphatase domain resulted in a statistically significantly elevated hearing threshold compared to wild-type mice which emphasized the role of the phosphatase domain in PPIP5K2 (PMID: 29590114), however this mechanism was not reflective of the missense variant reported in patients. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date September 17, 2025 (SOP Version 11).

hearing loss, autosomal recessive 100MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032740

Submitter: PanelApp Australia

hearing loss, autosomal recessive 100LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032740

Submitter: Ambry Genetics

hearing loss, autosomal recessive 100LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032740

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 100AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 29590114

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPIP5K2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 105

not providedTotal: 15

PPIP5K2-related disorderTotal: 10

Hearing loss, autosomal recessive 100Total: 2

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001276277.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	7 clinvar	5 clinvar	13
missense		1 clinvar	101 clinvar	1 clinvar	4 clinvar	107
nonsense			1 clinvar			1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	1	108	8	9	126

Highest pathogenic variant AF is 0.00011548924

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 88 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001276277.3	RefSeq	NP_001263206.1	30	MANE Select
ENST00000358359.8	Ensembl	ENSP00000351126.3	30	MANE Select
NM_001281471.3	RefSeq	NP_001268400.1	32	Standard
NM_001345871.2	RefSeq	NP_001332800.1	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Phosphatidylinositol signaling system - Homo sapiens (human)
inositol pyrophosphates biosynthesis
Metabolism
superpathway of inositol phosphate compounds
Synthesis of pyrophosphates in the cytosol

Biological Process

inositol metabolic process
phosphorylation
inositol phosphate biosynthetic process
inositol phosphate metabolic process

Molecular Function

inositol-1,3,4,5,6-pentakisphosphate kinase activity
inositol hexakisphosphate kinase activity
inositol heptakisphosphate kinase activity
inositol hexakisphosphate 5-kinase activity
ATP binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000321521
Coding exons: 29
Length: 92648
Individuals with no LoFs: 125631
Homozygous LoFs: 0
Heterozygous LoFs: 117
Defined: 125748
p: 0.000465

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.80	375	647	0.579	0.0000336	8012
Missense (PolyPhen)		63	206.36	0.3053		2523
Synonymous	0.806	197	212	0.930	0.0000105	2281
Loss of Function	2.78	43	67.7	0.636	0.00000402	846

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.00036	0.00032	rare
Ashkenazi Jewish	0.00022	0.00020	rare
East Asian	0.0011	0.0011	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00048	0.00047	rare
South Asian	0.00051	0.00046	rare
Other	0.00086	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Bifunctional inositol kinase that acts in concert with the IP6K kinases IP6K1, IP6K2 and IP6K3 to synthesize the diphosphate group-containing inositol pyrophosphates diphosphoinositol pentakisphosphate, PP-InsP5, and bis- diphosphoinositol tetrakisphosphate, (PP)2-InsP4. PP-InsP5 and (PP)2-InsP4, also respectively called InsP7 and InsP8, regulate a variety of cellular processes, including apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, insulin signaling and neutrophil activation. Phosphorylates inositol hexakisphosphate (InsP6) at positions 1 or 3 to produce PP-InsP5 which is in turn phosphorylated by IP6Ks to produce (PP)2-InsP4. Alternatively, phosphorylates at position 1 or 3 PP-InsP5, produced by IP6Ks from InsP6, to produce (PP)2-InsP4. {ECO:0000269|PubMed:17690096, ECO:0000269|PubMed:17702752}.;

Recessive Scores

pRec: 0.114

Intolerance Scores

LoFtool: 0.918
RVIS EVS: -0.19
RVIS percentile EVS: 39.24

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium