HNRNPH2

Chr XXLD

heterogeneous nuclear ribonucleoprotein H2

Also known as: FTP3, HNRPH', HNRPH2, MRXSB, NRPH2, hnRNPH'

NCBI Gene: 3188 ENSG00000126945 UniProt: P55795 OMIM: 300610

The protein binds to RNA through three quasi-RRM domains and influences pre-mRNA processing and other aspects of mRNA metabolism and transport in the nucleus. Loss-of-function mutations cause X-linked syndromic intellectual developmental disorder, Bain type, following an X-linked dominant inheritance pattern. The high pLI score (0.95) and low LOEUF score (0.31) indicate strong intolerance to loss-of-function variants, consistent with the pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA 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 three repeats of quasi-RRM domains that binds to RNAs. It is very similar to the family member HNRPH1. This gene is thought to be involved in Fabray disease and X-linked agammaglobulinemia phenotype. Alternative splicing results in multiple transcript variants encoding the same protein. Read-through transcription between this locus and the ribosomal protein L36a gene has been observed. [provided by RefSeq, Jan 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismXLDLOEUF 0.311 OMIM phenotype

Clinical Summary— HNRNPH2

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Gene-Disease Validity (ClinGen)

X-linked complex neurodevelopmental disorder · XLDefinitive

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 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 45 VUS of 86 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 →

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GeneReview available — HNRNPH2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.31LOEUF

pLI 0.954

Z-score 2.89

OE 0.00 (0.00–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.62Z-score

OE missense 0.24 (0.18–0.30)

42 obs / 178.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.31)

0≤0.351.4

Missense OE?0.24 (0.18–0.30)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 0 / 9.7Missense obs/exp: 42 / 178.1Syn Z: 0.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHNRNPH2-related neurodevelopmental disorderOTHERmonoallelic_X_heterozygous

This gene — mechanism propensity

0.3495th %ile

GOF

0.4382th %ile

LOF

0.78top 5%

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

LOFprediction above median · 27% of P/LP variants are LoF · LOEUF 0.31

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

86 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic9

VUS45

Likely Benign22

Benign2

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	5	0	0	6
Likely Pathogenic	3	6	0	0	9
VUS	2	41	1	1	45
Likely Benign	0	5	1	16	22
Benign	0	0	1	1	2
Conflicting	—				2
Total	6	57	3	18	86

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

View in ClinVar →

102 pathogenic / likely-pathogenic (of 114) ClinVar copy-number / structural variants overlap HNRNPH2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →