SOX5

Chr 12AD

SRY-box transcription factor 5

Also known as: L-SOX5, L-SOX5B, L-SOX5F, LAMSHF

NCBI Gene: 6660 ENSG00000134532 UniProt: P35711 OMIM: 604975

The SOX5 protein is a transcription factor that regulates embryonic development and cell fate determination, with particular involvement in chondrogenesis. Loss-of-function mutations cause Lamb-Shaffer syndrome, an autosomal dominant neurodevelopmental disorder. The gene is highly constrained against loss-of-function variants, indicating that haploinsufficiency is the mechanism underlying this condition.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. The encoded protein may play a role in chondrogenesis. A pseudogene of this gene is located on chromosome 8. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Lamb-Shaffer syndromeMIM #616803

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Lamb-Shaffer syndrome · AD · ClinGen 2022
Supportive · developmental and speech delay due to SOX5 deficiency · AD · Orphanet

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

0.19

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 5.52

OE 0.07 (0.03–0.19)

Highly constrained

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

Missense Constraint?

3.15Z-score

OE missense 0.57 (0.51–0.64)

244 obs / 427.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.19)

0≤0.351.4

Missense OE?0.57 (0.51–0.64)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 3 / 41.2Missense obs/exp: 244 / 427.3Syn Z: -0.21

Background carrier burden — how many people carry a rare variant somewhere in SOX5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

703 rare PASS variants

Rare truncating (LoF)

1 in 2,300

32 rare PASS variants

Rare synonymous (reference)

1 in 130

363 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SOX5. 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 180	1 in 2,200
South Asian	~43k	1 in 130	≈ 1 in 38,000
Remaining (unassigned)	~30k	1 in 88	1 in 620
European (Finnish)	~27k	1 in 280	1 in 4,500
Admixed American	~22k	1 in 170	≈ 1 in 5,300
African / African American	~21k	1 in 180	1 in 3,000
East Asian	~20k	1 in 180	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 230	none seen
Middle Eastern	~2,884	1 in 200	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): 13 of 15 coding exons well covered in gnomAD exomes; exons 4, 12 marginal. Genomes: all 15.? see exons ↓