ZRSR2

Chr X

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

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.

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.13

Clinical Summary— ZRSR2

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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· 32 VUS of 139 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 →

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?

0.13LOEUF

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

This gene — mechanism propensity

0.4388th %ile

GOF

0.6247th %ile

LOF

0.68top 10%

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

LOFprediction above median · 100% of P/LP variants are LoF · LOEUF 0.13

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

139 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic4

VUS32

Likely Benign12

Benign1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	0	0	2
Likely Pathogenic	4	0	0	0	4
VUS	0	30	2	0	32
Likely Benign	0	3	4	5	12
Benign	0	0	0	1	1
Total	6	33	6	6	51

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

View in ClinVar →

75 pathogenic / likely-pathogenic (of 93) ClinVar copy-number / structural variants overlap ZRSR2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →