SON

Chr 21AD

SON DNA and RNA binding protein

Also known as: BASS1, C21orf50, DBP-5, NREBP, SON3, TOKIMS

NCBI Gene: 6651 ENSG00000159140 UniProt: P18583 OMIM: 182465

The protein binds RNA and promotes pre-mRNA splicing, particularly for transcripts with poor splice sites. Loss-of-function mutations cause ZTTK syndrome, an autosomal dominant neurodevelopmental disorder. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the mechanism of disease.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that contains multiple simple repeats. The encoded protein binds RNA and promotes pre-mRNA splicing, particularly of transcripts with poor splice sites. The protein also recognizes a specific DNA sequence found in the human hepatitis B virus (HBV) and represses HBV core promoter activity. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.121 OMIM phenotype

Clinical Summary— SON

🧬

Gene-Disease Validity (ClinGen)

ZTTK syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

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.

📋

ClinVar Variants

154 unique Pathogenic / Likely Pathogenic· 764 VUS of 1776 total submissions

💊

Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SON

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?

0.12LOEUF

pLI 1.000

Z-score 7.74

OE 0.05 (0.02–0.12)

Highly constrained

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

Missense Constraint?

1.54Z-score

OE missense 0.88 (0.84–0.93)

1187 obs / 1346.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.12)

0≤0.351.4

Missense OE?0.88 (0.84–0.93)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 4 / 77.5Missense obs/exp: 1187 / 1346.1Syn Z: -3.65

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSON-related intellectual disability, congenital malformations, and failure to thriveLOFAD

This gene — mechanism propensity

0.18100th %ile

GOF

0.13100th %ile

LOF

0.84top 5%

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

LOFprediction above median · 1 literature citation · 95% of P/LP variants are LoF · LOEUF 0.12 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFDetailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 31005274 ↗

ClinVar Variant Classifications

1776 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic107

Likely Pathogenic47

VUS764

Likely Benign680

Benign103

Conflicting57

107

Pathogenic

Likely Pathogenic

764

VUS

680

Likely Benign

103

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	105	1	1	0	107
Likely Pathogenic	42	3	2	0	47
VUS	3	740	14	7	764
Likely Benign	1	235	25	419	680
Benign	2	61	18	22	103
Conflicting	—				57
Total	153	1,040	60	448	1,758

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

View in ClinVar →

65 pathogenic / likely-pathogenic (of 76) ClinVar copy-number / structural variants overlap SON — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

SON · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — SON

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Carcinoma, Non-Small-Cell LungNeoplasm Metastasis

A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer

RECRUITING

NCT06119581Phase PHASE3Eli Lilly and CompanyStarted 2023-12-21

LY3537982PembrolizumabPlacebo

Metastatic Solid TumorAdvanced Cancer

High Definition Medicine for Solid Tumors Oncology

RECRUITING

NCT06590506Centro Nacional de Investigaciones Oncologicas CARLOS IIIStarted 2023-03-02

Wearable

Chronic Migraine HeadacheRadiofrequency AblationGreater Occipital Nerve Block

The Effect of Interventional Procedures on Serum CGRP and PACAP-38 Levels in Chronic Migraine

ACTIVE NOT RECRUITING

NCT07395908Phase NAAydin Adnan Menderes UniversityStarted 2025-05-29