NHLH2

protein-coding

nescient helix-loop-helix 2, the group of Basic helix-loop-helix proteins

Gene summary

Enables sequence-specific double-stranded DNA binding activity and transcription coactivator binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within with a positive effect on apoptotic process; hypothalamus gonadotrophin-releasing hormone neuron development; and peripheral nervous system development. Predicted to act upstream of or within several processes, including cell migration in hindbrain; male gonad development; and male mating behavior. Predicted to be located in chromatin. Predicted to be part of transcription regulator complex. Implicated in hypogonadotropic hypogonadism. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

HEN2

MANE transcript

NM_005599.3

Inheritance

ClinVar variants

U:15B:2

Top phenotype

Hypogonadotropic hypogonadism 27 without anosmia

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:115,836,377-115,843,917

External References & Databases

Ensembl (ENSG00000177551)

Transcript & Mutation Effects

hg38 • Region Span ~7.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypogonadotropic hypogonadism 27 without anosmiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030684

Submitter: Labcorp Genetics (formerly Invitae)

hypogonadotropic hypogonadism 27 without anosmiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030684

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypogonadotropic hypogonadism 27 without anosmiaAR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: In Hypogonadotropic hypogonadism, surveillance in adolescence related to sexual maturation is indicated, as is monitoring of bone mineral density in order to allow early detection and treatment of disease

Refs: 35066646

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NHLH2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 13

Hypogonadotropic hypogonadismTotal: 4

Hypogonadotropic hypogonadism 27 without anosmiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005599.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				2 clinvar		2
missense			15 clinvar			15
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	15	2	0	17

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005599.3	RefSeq	NP_005590.1	1	MANE Select
ENST00000320238.3	Ensembl	ENSP00000322087.3	1	MANE Select
NM_001111061.2	RefSeq	NP_001104531.1	1	Standard
ENST00000369506.1	Ensembl	ENSP00000358519.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Prader-Willi and Angelman Syndrome

Biological Process

regulation of transcription by RNA polymerase II
central nervous system development
mating behavior
cell differentiation
ovulation cycle

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II activating transcription factor binding
DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

nucleus
transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369506
Coding exons: 1
Length: 7541
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.05	50	75.6	0.661	0.00000350	840
Missense (PolyPhen)		9	32.644	0.2757		352
Synonymous	-1.04	43	35.1	1.22	0.00000169	285
Loss of Function	1.52	0	2.68	0.00	1.18e-7	33

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May serve as DNA-binding protein and may be involved in the control of cell-type determination, possibly within the developing nervous system.;

Recessive Scores

pRec: 0.136

Intolerance Scores

RVIS EVS: 0.12
RVIS percentile EVS: 62.38

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Medium	Low	Medium
Cancer	Low	Low	Low