SOX3

Chr XX-linked

SRY-box transcription factor 3

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

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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismX-linkedLOEUF 0.852 OMIM phenotypes
Clinical SummarySOX3
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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

Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.18) despite low pLI — interpret in context.
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
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GeneReview available — SOX3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.85LOEUF
pLI 0.449
Z-score 1.79
OE 0.18 (0.060.85)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
2.21Z-score
OE missense 0.50 (0.410.60)
76 obs / 153.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.18 (0.060.85)
00.351.4
Missense OE0.50 (0.410.60)
00.61.4
Synonymous OE0.83
01.21.6
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
DN
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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

SOX3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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