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…

Primary Disease Associations & Inheritance

?Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2MIM #615422

Oculopharyngeal muscular dystrophy 2MIM #620460

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 · AD · ClinGen 2024

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

137

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.22

LOEUF· LoF intol.

LOF

Mechanism· predicted

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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

Background carrier burden — how many people carry a rare variant somewhere in HNRNPA2B1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 620

253 rare PASS variants

Rare truncating (LoF)

1 in 16,000

19 rare PASS variants

Rare synonymous (reference)

1 in 280

236 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HNRNPA2B1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 680	1 in 10,000
South Asian	~43k	1 in 310	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 790	none seen
European (Finnish)	~27k	1 in 1,600	≈ 1 in 13,000
Admixed American	~22k	1 in 960	none seen
African / African American	~21k	1 in 800	none seen
East Asian	~20k	1 in 810	none seen
Ashkenazi Jewish	~13k	≈ 1 in 3,300	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 10 coding exons well covered in gnomAD exomes and genomes.? see exons ↓