ZRSR2

Chr XXLR

zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2

Also known as: OFD21, U2AF1-RS2, U2AF1L2, U2AF1RS2, URP, ZC3H22

NCBI Gene: 8233 ENSG00000169249 UniProt: Q15696 OMIM: 300028

This gene encodes a pre-mRNA-binding protein required for splicing of both U2- and U12-type introns, specifically promoting recognition of 3'-splice sites and assembly of spliceosomal complexes. Mutations cause orofaciodigital syndrome XXI with X-linked recessive inheritance. The gene is highly constrained against loss-of-function variants (pLI >0.99), indicating intolerance to protein-truncating mutations.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an essential splicing factor. The encoded protein associates with the U2 auxiliary factor heterodimer, which is required for the recognition of a functional 3' splice site in pre-mRNA splicing, and may play a role in network interactions during spliceosome assembly. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Orofaciodigital syndrome XXIMIM #301132

XLR

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Orofaciodigital syndrome XXI; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.13

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 4.41

OE 0.00 (0.00–0.13)

Highly constrained

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

Missense Constraint?

1.46Z-score

OE missense 0.71 (0.61–0.81)

137 obs / 194.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.13)

0≤0.351.4

Missense OE?0.71 (0.61–0.81)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 0 / 22.7Missense obs/exp: 137 / 194.1Syn Z: 0.28

Background carrier burden — how many people carry a rare variant somewhere in ZRSR2?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

333 rare PASS variants

Rare truncating (LoF)

1 in 450

22 rare PASS variants

Rare synonymous (reference)

1 in 210

173 rare PASS variants

Rare missense and truncating variants are carried at similar rates in ZRSR2; this gene does not show strong loss-of-function constraint by this measure. 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)	~561k	1 in 190	1 in 460
South Asian	~36k	1 in 110	1 in 1,100
Remaining (unassigned)	~31k	1 in 110	1 in 550
European (Finnish)	~27k	1 in 350	1 in 1,400
Admixed American	~23k	1 in 360	1 in 660
African / African American	~21k	1 in 200	1 in 370
East Asian	~20k	1 in 180	1 in 2,400
Ashkenazi Jewish	~13k	1 in 980	1 in 480
Middle Eastern	~2,758	1 in 220	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 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓