SPEF2

protein-coding

sperm flagellar 2

Gene summary

Involved in sperm axoneme assembly. Located in sperm flagellum. Implicated in spermatogenic failure 43. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_024867.4

Inheritance

AR, AD

ClinVar variants

P:13U:288B:55

Top phenotype

Spermatogenic failure 43

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr5:35,617,844-35,814,611

External References & Databases

Ensembl (ENSG00000152582)

Transcript & Mutation Effects

hg38 • Region Span ~196.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spermatogenic failure 43STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032898

Submitter: PanelApp Australia

non-syndromic male infertility due to sperm motility disorderSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017173

Submitter: Orphanet

primary ciliary dyskinesiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016575

Submitter: ClinGen

*SPEF2* was first described as a primary ciliary dyskinesia (PCD)-causing gene in 2020 (Cindrić et al., PMID: 31545650). Variants in *SPEF2* had also been previously identified in individuals affected with multiple morphologic abnormalities of the flagella (PMID: 31151990) and asserted as a monogenic cause of spermatogenic failure 43 (MIM#: 618751). Probands diagnosed with spermatogenic failure displayed male infertility and reduced sperm motility, often without reported details of respiratory examinations, but sometimes in the confirmed absence of respiratory features (PMID: 31048344). Those diagnosed with primary ciliary dyskinesia exhibited respiratory symptoms including chronic rhinitis or sinusitis, bronchiectasis, productive/wet cough, and otitis media, in addition to infertility and reduced sperm motility (PMID: 31942643). Per the recommendations of the ClinGen Lumping & Splitting Working Group, the GCEP found consistencies between the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic SPEF2 loss-of-function) between patients diagnosed with either infertility or primary ciliary dyskinesia, while their overlapping phenotypes formed a single spectrum that included both infertility and respiratory features. As. a result, the GCEP recommended lumping of all SPEF2-related cases into a single gene curation under the broader disease entity primary ciliary dyskinesia (MONDO:0016575). This curation includes eleven variants (six frameshift, three nonsense, one missense, and one splice site) that have been reported in eight probands in five publications (PMIDs: 36615117, 31545650, 36873931, 31942643, 31048344). Overall, the mechanism of pathogenicity appears to be biallelic loss-of-function. This gene-disease relationship is also supported by multiple forms of experimental evidence ranging from expression to animal models (PMIDs: 31545650 and 21715716). PCD probands with *HYDIN* variants show SPEF2 expression / localization defects by immunofluorescence (PMID: 31545650). In addition, the mouse "big giant head" (bgh) model with homozygous *Spef2* disruption is characterized not only by hydrocephalus but also male infertility, abnormal ciliary motility, sinusitis and reduced respiratory ciliary beating frequency, which recapitulated the phenotypes found in human probands (PMID: 21715716). In conclusion, *SPEF2* is definitively associated with primary ciliary dyskinesia. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the Motile Ciliopathy GCEP on January 9th, 2025 (SOP Version 11).

spermatogenic failure 43STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032898

Submitter: Ambry Genetics

spermatogenic failure 43STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032898

Submitter: Labcorp Genetics (formerly Invitae)

primary ciliary dyskinesiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spermatogenic failure 43AR

Manifestation: Genitourinary

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31048344; 31151990; 31278745

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPEF2 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 283

not providedTotal: 54

SPEF2-related disorderTotal: 15

Spermatogenic failure 43Total: 14

not specifiedTotal: 12

Primary ciliary dyskinesiaTotal: 2

SchizophreniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024867.4. 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				17 clinvar	4 clinvar	21
missense			284 clinvar	26 clinvar	8 clinvar	318
nonsense	2 clinvar	2 clinvar	1 clinvar			5
start loss						0
frameshift	5 clinvar	1 clinvar				6
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	3 clinvar			6
Total	8	5	288	43	12	356

Highest pathogenic variant AF is 0.000009584249

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024867.4	RefSeq	NP_079143.3	37	MANE Select
ENST00000356031.8	Ensembl	ENSP00000348314.3	37	MANE Select
NM_144722.4	RefSeq	NP_653323.1	10	Standard
ENST00000282469.10	Ensembl	ENSP00000282469.6	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

spermatogenesis
cell differentiation

Cellular Component

Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356031
Coding exons: 37
Length: 196768
Individuals with no LoFs: 125570
Homozygous LoFs: 0
Heterozygous LoFs: 178
Defined: 125748
p: 0.000708

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.01	1008	922	1.09	0.0000467	12026
Missense (PolyPhen)		379	330.75	1.1459		4292
Synonymous	1.03	290	313	0.926	0.0000156	3286
Loss of Function	3.90	56	97.6	0.574	0.00000509	1236

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00039	0.00037	rare
Latino/Admixed American	0.0011	0.0010	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.0017	0.0015	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00070	0.00068	rare
South Asian	0.00082	0.00078	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for correct axoneme development in spermatozoa. Important for normal development of the manchette and sperm head morphology. Essential for male fertility. Plays a role in localization of the intraflagellar transport protein IFT20 to the manchette, suggesting function as an adapter for dynein-mediated protein transport during spermatogenesis. Also plays a role in bone growth where it seems to be required for normal osteoblast differentiation. {ECO:0000250|UniProtKB:Q8C9J3}.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.972
RVIS EVS: 2.82
RVIS percentile EVS: 99.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0147

Gene Damage Prediction

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