SPAG1

Chr 8AR

sperm associated antigen 1

Also known as: CILD28, CT140, DNAAF13, HEL-S-268, HSD-3.8, SP75, TPIS

NCBI Gene: 6674 ENSG00000104450 UniProt: Q07617 OMIM: 603395

SPAG1 encodes a GTPase that binds GTP and is involved in cytoplasmic assembly of ciliary dynein arms, with additional roles in spermatogenesis and fertilization. Mutations cause primary ciliary dyskinesia type 28, inherited in an autosomal recessive pattern. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The correlation of anti-sperm antibodies with cases of unexplained infertility implicates a role for these antibodies in blocking fertilization. Improved diagnosis and treatment of immunologic infertility, as well as identification of proteins for targeted contraception, are dependent on the identification and characterization of relevant sperm antigens. The protein expressed by this gene is recognized by anti-sperm agglutinating antibodies from an infertile woman. Furthermore, immunization of female rats with the recombinant human protein reduced fertility. This protein localizes to the plasma membrane of germ cells in the testis and to the post-acrosomal plasma membrane of mature spermatozoa. Recombinant polypeptide binds GTP and exhibits GTPase activity. Thus, this protein may regulate GTP signal transduction pathways involved in spermatogenesis and fertilization. Two transcript variants of this gene encode the same protein. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.761 OMIM phenotype

Clinical Summary— SPAG1

🧬

Gene-Disease Validity (ClinGen)

primary ciliary dyskinesia 28 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

73 unique Pathogenic / Likely Pathogenic· 233 VUS of 630 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — SPAG1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.76LOEUF

pLI 0.000

Z-score 2.75

OE 0.53 (0.37–0.76)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.91Z-score

OE missense 0.88 (0.81–0.95)

376 obs / 428.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.53 (0.37–0.76)

0≤0.351.4

Missense OE?0.88 (0.81–0.95)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 21 / 39.7Missense obs/exp: 376 / 428.9Syn Z: 2.20

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSPAG1-related primary ciliary dyskinesia associated with defective outer and inner dynein armsLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7229th %ile

GOF

0.6736th %ile

LOF

0.2189th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

630 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56

Likely Pathogenic17

VUS233

Likely Benign217

Benign55

Conflicting19

Pathogenic

Likely Pathogenic

233

VUS

217

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	46	1	9	0	56
Likely Pathogenic	16	0	1	0	17
VUS	5	217	10	1	233
Likely Benign	0	15	88	114	217
Benign	0	6	44	5	55
Conflicting	—				19
Total	67	239	152	120	597

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 47) ClinVar copy-number / structural variants overlap SPAG1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →