HNRNPD

protein-coding

heterogeneous nuclear ribonucleoprotein D, the group of Heterogeneous nuclear ribonucleoproteins|RNA binding motif containing

Gene summary

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are nucleic acid binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. It localizes to both the nucleus and the cytoplasm. This protein is implicated in the regulation of mRNA stability. Alternative splicing of this gene results in four transcript variants. [provided by RefSeq, Jul 2008]

Previous symbols:

AUF1
HNRPD

MANE transcript

NM_031370.3

Inheritance

ClinVar variants

P:4U:43B:2

Top phenotype

complex neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr4:82,352,498-82,374,503

External References & Databases

Ensembl (ENSG00000138668)

Transcript & Mutation Effects

hg38 • Region Span ~22.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*HNRNPD* encodes a nuclear ribonucleoprotein implicated in mRNA processing mechanisms. *HNRNPD* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2021 (Gillentine et al., PMID: 33874999). Reported phenotypes include developmental delay, intellectual disability, speech and language delay, autism spectrum disorder, brain imaging abnormalities, growth delay, hypotonia, seizures, dystonia, dysmorphic facial features, and hand and feet abnormalities. Additional case reports with detailed clinical information are needed to better understand the phenotype spectrum. Fourteen variants (frameshift, nonsense, splice, and single gene deletion) that have been reported in 17 probands in four publications (PMIDs: 24768552, 33057194, 33874999, 35982159) are included in this curation. Thirteen occurred *de novo* and four were of unknown inheritance. *HNRNPD* is significantly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.22, gnomAD v4.1.0). The fact that the majority of the reported variants are nonsense, frameshift or splice variants is consistent with a loss-of-function mechanism, but no functional studies have been performed. This gene-disease relationship is also supported by biochemical function and protein interaction. *HNRNPD* belongs to the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family; several genes in this family (*HNRNPC*, *HNRNPH1*, *HNRNPH2*, *HNRNPK*, *SYNCRIP* [also known as *HNRNPQ*], *HNRNPR*, and *HNRNPU*) have recently been implicated in neurodevelopmental disorders with overlapping clinical features, including developmental delay, intellectual disability, autism spectrum disorder, epilepsy, and congenital anomalies. In summary, there is definitive evidence supporting the relationship between *HNRNPD* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 17, 2025 (SOP Version 11).

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HNRNPD variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 38

not providedTotal: 4

HNRNPD-related disorderTotal: 4

Neurodevelopmental disorderTotal: 2

Intellectual disabilityTotal: 2

HNRNPD-related neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031370.3. 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				2 clinvar		2
missense			37 clinvar			37
nonsense		2 clinvar	1 clinvar			3
start loss						0
frameshift	1 clinvar	1 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	3	43	2	0	49

Highest pathogenic variant AF is 0.000001299437

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 110 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_031370.3	RefSeq	NP_112738.1	8	MANE Select
ENST00000313899.12	Ensembl	ENSP00000313199.7	8	MANE Select
NM_001003810.2	RefSeq	NP_001003810.1	6	Standard
NM_002138.4	RefSeq	NP_002129.2	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mRNA Processing
AUF1 (hnRNP D0) binds and destabilizes mRNA
Metabolism of RNA
mRNA Splicing - Major Pathway
Regulation of mRNA stability by proteins that bind AU-rich elements

Biological Process

mRNA splicing, via spliceosome
liver development
regulation of transcription, DNA-templated
RNA processing
RNA catabolic process

Molecular Function

AT DNA binding
chromatin binding
RNA binding
mRNA binding
protein binding

Cellular Component

nucleus
nucleoplasm
cytosol
synapse
ribonucleoprotein complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000313899
Coding exons: 8
Length: 22006
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125742
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.45	91	185	0.492	0.00000885	2316
Missense (PolyPhen)		16	69.378	0.23062		890
Synonymous	1.48	50	65.1	0.768	0.00000342	648
Loss of Function	4.03	1	20.9	0.0479	0.00000106	253

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds with high affinity to RNA molecules that contain AU-rich elements (AREs) found within the 3'-UTR of many proto- oncogenes and cytokine mRNAs. Also binds to double- and single- stranded DNA sequences in a specific manner and functions a transcription factor. Each of the RNA-binding domains specifically can bind solely to a single-stranded non-monotonous 5'-UUAG-3' sequence and also weaker to the single-stranded 5'-TTAGGG-3' telomeric DNA repeat. Binds RNA oligonucleotides with 5'-UUAGGG-3' repeats more tightly than the telomeric single-stranded DNA 5'- TTAGGG-3' repeats. Binding of RRM1 to DNA inhibits the formation of DNA quadruplex structure which may play a role in telomere elongation. May be involved in translationally coupled mRNA turnover. Implicated with other RNA-binding proteins in the cytoplasmic deadenylation/translational and decay interplay of the FOS mRNA mediated by the major coding-region determinant of instability (mCRD) domain. May play a role in the regulation of the rhythmic expression of circadian clock core genes. Directly binds to the 3'UTR of CRY1 mRNA and induces CRY1 rhythmic translation. May also be involved in the regulation of PER2 translation. {ECO:0000269|PubMed:10080887, ECO:0000269|PubMed:11051545, ECO:0000269|PubMed:24423872}.;

Recessive Scores

pRec: 0.426

Intolerance Scores

LoFtool: 0.160
RVIS EVS: -0.01
RVIS percentile EVS: 52.85

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.903

Gene Damage Prediction

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