HNRNPUL2

Chr 11

heterogeneous nuclear ribonucleoprotein U like 2

Also known as: HNRPUL2, SAF-A2

NCBI Gene: 221092 ENSG00000214753 UniProt: Q1KMD3

HNRNPUL2 encodes an RNA-binding protein that regulates alternative mRNA splicing within the nucleus and is extremely intolerant to loss-of-function variants (pLI=1.0, LOEUF=0.23). Mutations cause autosomal dominant developmental and epileptic encephalopathy with early infantile onset, characterized by severe intellectual disability, seizures, and developmental delay. The gene's extreme constraint suggests that even heterozygous mutations can cause significant neurological dysfunction.

ResearchSummary from RefSeq

Enables RNA binding activity. Predicted to be involved in alternative mRNA splicing, via spliceosome. Located in nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

Clinical highlights

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.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

0.23

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 5.62

OE 0.11 (0.06–0.23)

Highly constrained

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

Missense Constraint?

0.96Z-score

OE missense 0.87 (0.79–0.95)

355 obs / 409.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.23)

0≤0.351.4

Missense OE?0.87 (0.79–0.95)

0≤0.61.4

Synonymous OE?1.31

0≤1.21.6

LoF obs/exp: 5 / 46.3Missense obs/exp: 355 / 409.4Syn Z: -3.07

Background carrier burden — how many people carry a rare variant somewhere in HNRNPUL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 76

1,003 rare PASS variants

Rare truncating (LoF)

1 in 5,500

60 rare PASS variants

Rare synonymous (reference)

1 in 81

482 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HNRNPUL2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 6,700
South Asian	~43k	1 in 60	≈ 1 in 13,000
Remaining (unassigned)	~30k	1 in 57	≈ 1 in 7,000
European (Finnish)	~27k	1 in 280	1 in 4,000
Admixed American	~22k	1 in 63	1 in 1,800
African / African American	~21k	1 in 75	1 in 3,000
East Asian	~20k	1 in 87	1 in 1,100
Ashkenazi Jewish	~13k	1 in 720	≈ 1 in 5,700
Middle Eastern	~2,884	1 in 78	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): 14 of 14 coding exons well covered in gnomAD exomes. Genomes: 13 of 14 (exon 14 below).? see exons ↓