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…

Primary Disease Associations & Inheritance

ZTTK syndromeMIM #617140

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · ZTTK syndrome · AD · ClinGen 2025

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

865

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.12

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

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

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 24

2,953 rare PASS variants

Rare truncating (LoF)

1 in 1,300

54 rare PASS variants

Rare synonymous (reference)

1 in 31

1,344 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SON. 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 29	1 in 1,600
South Asian	~43k	1 in 22	1 in 1,900
Remaining (unassigned)	~30k	1 in 25	1 in 1,000
European (Finnish)	~27k	1 in 94	1 in 2,000
Admixed American	~22k	1 in 21	1 in 980
African / African American	~21k	1 in 21	1 in 250
East Asian	~20k	1 in 24	1 in 2,800
Ashkenazi Jewish	~13k	1 in 55	1 in 2,400
Middle Eastern	~2,884	1 in 28	≈ 1 in 1,300

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): 8 of 12 coding exons well covered in gnomAD exomes; exons 7, 8, 11, 12 marginal. Genomes: 10 of 12 (exons 4, 12 below).? see exons ↓