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…

LOFmechanismADLOEUF 0.191 OMIM phenotype

Clinical Summary— SOX5

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Gene-Disease Validity (ClinGen)

Lamb-Shaffer syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

91 unique Pathogenic / Likely Pathogenic· 163 VUS of 328 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSOX5-related 12p12.5 intragenic deletions associated with intellectual disabilityLOFAD

This gene — mechanism propensity

0.3296th %ile

GOF

0.3193th %ile

LOF

0.84top 5%

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

LOFprediction above median · 1 literature citation · 65% of P/LP variants are LoF · LOEUF 0.19 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFClinical and genetic characterization of a patient with SOX5 haploinsufficiency caused by a de novo balanced reciprocal translocation.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 29477873 ↗

ClinVar Variant Classifications

328 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55

Likely Pathogenic36

VUS163

Likely Benign48

Benign6

Conflicting4

Pathogenic

Likely Pathogenic

163

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	43	4	8	0	55
Likely Pathogenic	16	19	1	0	36
VUS	4	147	9	3	163
Likely Benign	2	17	6	23	48
Benign	0	0	2	4	6
Conflicting	—				4
Total	65	187	26	30	312

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

View in ClinVar →

64 pathogenic / likely-pathogenic (of 90) ClinVar copy-number / structural variants overlap SOX5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →