HNRNPH1

Chr 5AD

heterogeneous nuclear ribonucleoprotein H1

Also known as: HNRPH, HNRPH1, NEDCDS, hnRNPH

NCBI Gene: 3187 ENSG00000169045 UniProt: P31943 OMIM: 601035

HNRNPH1 encodes a heterogeneous nuclear ribonucleoprotein that binds RNA and regulates pre-mRNA alternative splicing, serving as a component of hnRNP complexes that process pre-mRNAs before they become functional cytoplasmic mRNAs. Mutations cause autosomal dominant neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.11), indicating intolerance to reduced gene dosage.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of a subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins that complex with heterogeneous nuclear RNA. 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 may shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has three repeats of quasi-RRM domains that bind to RNA and is very similar to the family member HNRPF. This gene may be associated with hereditary lymphedema type I. Alternatively spliced transcript variants have been described [provided by RefSeq, Mar 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.111 OMIM phenotype

Clinical Summary— HNRNPH1

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 67 VUS of 116 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 4.84

OE 0.00 (0.00–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

4.09Z-score

OE missense 0.29 (0.24–0.35)

74 obs / 259.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.11)

0≤0.351.4

Missense OE?0.29 (0.24–0.35)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 0 / 27.3Missense obs/exp: 74 / 259.3Syn Z: -0.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHNRNPH1-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.3892th %ile

GOF

0.4580th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 56% of P/LP variants are LoF · LOEUF 0.11

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

116 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic3

VUS67

Likely Benign10

Benign4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	3	0	0	6
Likely Pathogenic	2	1	0	0	3
VUS	6	56	5	0	67
Likely Benign	0	1	2	7	10
Benign	0	0	2	2	4
Total	11	61	9	9	90

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

25 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap HNRNPH1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →