NR5A1

Chr 9AD

nuclear receptor subfamily 5 group A member 1

Also known as: AD4BP, ELP, FTZ1, FTZF1, POF7, SF-1, SF1, SPGF8

NCBI Gene: 2516 ENSG00000136931 UniProt: Q13285

The protein encoded by this gene is a transcriptional activator involved in sex determination. The encoded protein binds DNA as a monomer. Defects in this gene are a cause of XY sex reversal with or without adrenal failure as well as adrenocortical insufficiency without ovarian defect. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

46XX sex reversal 4MIM #617480

46XY sex reversal 3MIM #612965

Adrenocortical insufficiencyMIM #612964

Premature ovarian failure 7MIM #612964

Spermatogenic failure 8MIM #613957

UniProt46,XY sex reversal 3

UniProt46,XX sex reversal 4

UniProtAdrenal insufficiency, NR5A1-related

Active trials

161

Pathogenic / LP

384

ClinVar variants

Pubs (1 yr)

2.3

Missense Z

0.26

LOEUF· LoF intolerant

Clinical Summary— NR5A1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

161 Pathogenic / Likely Pathogenic· 116 VUS of 384 total submissions

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GeneReview available — NR5A1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.26LOEUF

pLI 0.990

Z-score 3.73

OE 0.06 (0.02–0.26)

Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.34Z-score

OE missense 0.61 (0.54–0.69)

175 obs / 286.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.02–0.26)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.54–0.69)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02

0≤1.21.6

LoF obs/exp: 1 / 18.1Missense obs/exp: 175 / 286.2Syn Z: -0.20

0.3991th %ile

GOF

0.3491th %ile

LOF

0.72top 10%

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

LOFprediction above median · 1 literature citation · 27% of P/LP variants are LoF · LOEUF 0.26

Literature Evidence

LOFWe identified a partial NR5A1 deletion affecting exons 2 and 3, leading to NR5A1 haploinsufficiency in 1 patient presenting with female external genitalia with clitoromegaly, absence of a uterus, and mildly dysgenetic testes.PMID:21654157

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.