SOX3

Chr X

SRY-box transcription factor 3

Also known as: GHDX, MRGH, PHP, PHPX, SOXB

NCBI Gene: 6658 ENSG00000134595 UniProt: P41225

SOX3 encodes a transcription factor required for formation of the hypothalamo-pituitary axis and functions as a neuronal developmental switch by keeping neural cells undifferentiated and suppressing neuronal differentiation. X-linked loss-of-function mutations cause intellectual developmental disorder with isolated growth hormone deficiency or panhypopituitarism. The pathogenic mechanism involves loss of function of this essential transcriptional regulator.

GeneReviews 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. Mutations in this gene have been associated with X-linked cognitive disability with growth hormone deficiency. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.85

Clinical Summary— SOX3

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Gene-Disease Validity (ClinGen)

SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder · XLModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.18) despite low pLI — interpret in context.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 75 VUS of 127 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SOX3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.449

Z-score 1.79

OE 0.18 (0.06–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.21Z-score

OE missense 0.50 (0.41–0.60)

76 obs / 153.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.18 (0.06–0.85)

0≤0.351.4

Missense OE?0.50 (0.41–0.60)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 1 / 5.5Missense obs/exp: 76 / 153.0Syn Z: 1.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSOX3-related intellectual developmental disorder with isolated growth hormone deficiencyLOFXLR

definitiveSOX3-related sex reversalOTHERmonoallelic_X_heterozygous

This gene — mechanism propensity

0.4785th %ile

GOF

0.3491th %ile

LOF

0.81top 5%

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

LOFprediction above median

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

127 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic1

VUS75

Likely Benign34

Benign4

Conflicting8

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	3	0	5
Likely Pathogenic	0	1	0	0	1
VUS	0	71	1	3	75
Likely Benign	0	11	3	20	34
Benign	0	1	0	3	4
Conflicting	—				8
Total	0	86	7	26	127

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

View in ClinVar →

110 pathogenic / likely-pathogenic (of 116) ClinVar copy-number / structural variants overlap SOX3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →