SOX18

Chr 20ARAD

SRY-box transcription factor 18

Also known as: HLTRS, HLTS

NCBI Gene: 54345 ENSG00000203883 OMIM: 601618

SOX18 encodes a transcription factor that activates genes essential for embryonic cardiovascular development, lymphangiogenesis, and hair development by binding to specific promoter sequences. Mutations cause hypotrichosis-lymphedema-telangiectasia syndrome, with or without renal defects, characterized by sparse hair, lymphatic abnormalities, and dilated blood vessels. The condition follows both autosomal recessive and autosomal dominant inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. This protein plays a role in hair, blood vessel, and lymphatic vessel development. Mutations in this gene have been associated with recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 1.052 OMIM phenotypes

Clinical Summary— SOX18

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 156 VUS of 224 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.151

Z-score 1.50

OE 0.34 (0.14–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.86Z-score

OE missense 0.79 (0.67–0.93)

104 obs / 131.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.14–1.05)

0≤0.351.4

Missense OE?0.79 (0.67–0.93)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 2 / 6.0Missense obs/exp: 104 / 131.8Syn Z: -0.00

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSOX18-related hypotrichosis-lymphoedema-telangiectasia syndromeOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6065th %ile

GOF

0.5858th %ile

LOF

0.51top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNFunctional analysis confirmed that SOX18wt has potent trans-activation properties, while SOX18DN displays dominant-negative effect.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 24460943 ↗

ClinVar Variant Classifications

224 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic5

VUS156

Likely Benign47

Benign7

Conflicting6

Pathogenic

Likely Pathogenic

156

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	5	0	0	0	5
VUS	3	149	4	0	156
Likely Benign	0	6	3	38	47
Benign	0	1	4	2	7
Conflicting	—				6
Total	9	158	11	40	224

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap SOX18 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →