DMRT1

Chr 9

doublesex and mab-3 related transcription factor 1

Also known as: CT154, DMT1

NCBI Gene: 1761 ENSG00000137090 UniProt: Q9Y5R6 OMIM: 602424

DMRT1 encodes a transcription factor that controls male sex determination and testis development by regulating spermatogonial cell proliferation and preventing meiosis in undifferentiated germ cells. Mutations cause disorders of sex development, specifically XY gonadal dysgenesis with defective testicular development and feminization in individuals with XY chromosomes. The gene shows autosomal inheritance and is highly constrained against loss-of-function mutations (LOEUF 0.479), reflecting its critical role in male sexual development.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene is found in a cluster with two other members of the gene family, having in common a zinc finger-like DNA-binding motif (DM domain). The DM domain is an ancient, conserved component of the vertebrate sex-determining pathway that is also a key regulator of male development in flies and nematodes. This gene exhibits a gonad-specific and sexually dimorphic expression pattern. Defective testicular development and XY feminization occur when this gene is hemizygous. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.48

Clinical Summary— DMRT1

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Gene-Disease Validity (ClinGen)

spermatogenic failure · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.74) — some intolerance to loss-of-function variants.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 75 VUS of 155 total submissions

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GeneReview available — DMRT1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.739

Z-score 2.85

OE 0.15 (0.06–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.44Z-score

OE missense 1.08 (0.97–1.21)

234 obs / 215.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.15 (0.06–0.48)

0≤0.351.4

Missense OE?1.08 (0.97–1.21)

0≤0.61.4

Synonymous OE?1.48

0≤1.21.6

LoF obs/exp: 2 / 13.2Missense obs/exp: 234 / 215.9Syn Z: -3.60

This gene — mechanism propensity

0.4388th %ile

GOF

0.2597th %ile

LOF

0.79top 5%

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

LOFprediction above median · 33% of P/LP variants are LoF · LOEUF 0.48

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

ClinVar Variant Classifications

155 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic9

VUS75

Likely Benign28

Benign37

Conflicting2

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	0	0	0	0
Likely Pathogenic	3	6	0	0	9
VUS	0	70	5	0	75
Likely Benign	0	2	7	19	28
Benign	0	3	26	8	37
Conflicting	—				2
Total	3	81	38	27	151

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

View in ClinVar →

178 pathogenic / likely-pathogenic (of 218) ClinVar copy-number / structural variants overlap DMRT1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →