FSIP2

Chr 2AR

fibrous sheath interacting protein 2

Also known as: SPGF34

NCBI Gene: 401024ENSG00000188738UniProt: Q5CZC0

This gene encodes a protein associated with the sperm fibrous sheath. Genes encoding most of the fibrous-sheath associated proteins genes are transcribed only during the postmeiotic period of spermatogenesis. The protein encoded by this gene is specific to spermatogenic cells. Copy number variation in this gene may be associated with testicular germ cell tumors. Pseudogenes associated with this gene are reported on chromosomes 2 and X. [provided by RefSeq, Aug 2016]

Primary Disease Associations & Inheritance

Spermatogenic failure 34MIM #618153
AR
488
ClinVar variants
5
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— FSIP2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
5 Pathogenic / Likely Pathogenic· 443 VUS of 488 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
0.51LOEUF
pLI 0.000
Z-score 7.35
OE 0.43 (0.35–0.51)
Moderately constrained

More LoF-intolerant than ~75% 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.
3.31Z-score
OE missense 0.83 (0.80–0.86)
2489 obs / 2998.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.43 (0.35–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.80–0.86)
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.0.85
0≤1.21.6
LoF obs/exp: 81 / 190.4Missense obs/exp: 2489 / 2998.7Syn Z: 3.77

ClinVar Variant Classifications

488 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3
Likely Pathogenic2
VUS443
Likely Benign40
3
Pathogenic
2
Likely Pathogenic
443
VUS
40
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
2
0
3
Likely Pathogenic
0
0
2
0
2
VUS
2
433
8
0
443
Likely Benign
0
38
1
1
40
Benign
0
0
0
0
0
Total3471131488

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

View in ClinVar →

Protein Context — Lollipop Plot

FSIP2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spermatogenic failure 34

MIM #618153

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole exome sequencing analysis of 167 men with primary infertility.
Zhou H et al.·BMC Med Genomics
2024
Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer.
Liu ZX et al.·JAMA Netw Open
2022Cohort
Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia.
Malcher A et al.·Andrology
2022
Novel variants of FSIP2 and SPEF2 cause varying degrees of spermatozoa damage in MMAF patients and favorable ART outcomes.
Dai CL et al.·J Assist Reprod Genet
2025Cohort
Novel Compound Heterozygous Mutation in FSIP2 Causes Multiple Morphological Abnormalities of the Sperm Flagella (MMAF) and Male Infertility.
Hou M et al.·Reprod Sci
2022Case report
Genome-Wide and Rare Variant Association Studies of Amblyopia in the All of Us Research Program.
Lee KAV et al.·Ophthalmology
2025
Identifying potential genetic biomarkers for sperm dysfunction through whole-genome sequencing.
Khan MR et al.·Sci Rep
2025
[Clinical and genetic analysis of a patient with FSIP2 compound heterozygous variants causing multiple morphological abnormalities of sperm flagella].
Chen YQ et al.·Zhonghua Nan Ke Xue
2025Case report
Novel mutations in FSIP2 cause male infertility through multiple morphological abnormalities of the sperm flagella.
Hussain M et al.·Asian J Androl
2026Case report
METTL5 deficiency induces oligoasthenoteratozoospermia via impaired 18S rRNA m(6)A methylation in humans and mice.
Zhang M et al.·Mol Ther
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools