HNRNPA2B1

Chr 7AD

heterogeneous nuclear ribonucleoprotein A2/B1

Also known as: HNRNPA2, HNRNPB1, HNRPA2, HNRPA2B1, HNRPB1, IBMPFD2, OPDM2, OPMD2

NCBI Gene: 3181 ENSG00000122566 UniProt: P22626 OMIM: 600124

This protein binds RNA and packages nascent pre-mRNAs into ribonucleoprotein particles, regulates mRNA splicing and transport, and processes microRNAs by recognizing methylated adenosine marks. Mutations cause autosomal dominant inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia, and oculopharyngeal muscular dystrophy. The pathogenic mechanism involves loss of function of this highly constrained protein.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene belongs to the A/B 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 two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.222 OMIM phenotypes

Clinical Summary— HNRNPA2B1

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Gene-Disease Validity (ClinGen)

inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 · ADModerate

Moderate evidence — consider for supplementary testing

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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

6 unique Pathogenic / Likely Pathogenic· 103 VUS of 434 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HNRNPA2B1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.22LOEUF

pLI 0.997

Z-score 4.13

OE 0.05 (0.01–0.22)

Highly constrained

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

Missense Constraint?

3.00Z-score

OE missense 0.39 (0.32–0.47)

75 obs / 192.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.01–0.22)

0≤0.351.4

Missense OE?0.39 (0.32–0.47)

0≤0.61.4

Synonymous OE?1.86

0≤1.21.6

LoF obs/exp: 1 / 21.8Missense obs/exp: 75 / 192.1Syn Z: -5.37

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHNRNPA2B1-related early-onset oculopharyngeal muscular dystrophyOTHERAD

This gene — mechanism propensity

0.4289th %ile

GOF

0.3293th %ile

LOF

0.78top 5%

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

LOFprediction above median · 50% of P/LP variants are LoF · LOEUF 0.22

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

434 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS103

Likely Benign266

Benign28

Conflicting3

Pathogenic

Likely Pathogenic

103

VUS

266

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	1	0	0	4
Likely Pathogenic	0	2	0	0	2
VUS	8	69	24	2	103
Likely Benign	0	3	159	104	266
Benign	0	0	25	3	28
Conflicting	—				3
Total	11	75	208	109	406

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap HNRNPA2B1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →