ROPN1

Chr 3

rhophilin associated tail protein 1

Also known as: CT91, ODF6, RHPNAP1, ROPN1A, ropporin

NCBI Gene: 54763 ENSG00000065371 UniProt: Q9HAT0 OMIM: 611757

The protein is a component of the sperm fibrous sheath that interacts with signaling proteins including rhophilin and A-kinase anchoring proteins to regulate sperm motility and capacitation. Loss-of-function mutations cause male infertility due to defective sperm function. The gene shows low constraint against loss-of-function variants, and inheritance would be autosomal recessive for male infertility phenotypes.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is found in the fibrous sheath of spermatazoa, where it interacts with rhophilin, a Rho GTPase binding protein. The encoded protein also can bind an A-kinase anchoring protein (AKAP110) and a calcium-binding tyrosine phosphorylation-regulated protein (CABYR). This protein may be involved in sperm motility and has been shown to be a cancer-testis antigen in hematologic malignancies. Several transcript variants, some protein-coding and some non-protein coding, have been found for this gene. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.42

Clinical Summary— ROPN1

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

36 VUS of 43 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.42LOEUF

pLI 0.000

Z-score 0.67

OE 0.76 (0.43–1.42)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.07Z-score

OE missense 0.98 (0.84–1.15)

116 obs / 118.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.43–1.42)

0≤0.351.4

Missense OE?0.98 (0.84–1.15)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 7 / 9.2Missense obs/exp: 116 / 118.2Syn Z: -0.31

This gene — mechanism propensity

0.6454th %ile

GOF

0.6832th %ile

LOF

0.2873th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

43 submitted variants in ClinVar

ClinVar

Classification Summary

VUS36

Likely Benign4

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	36	0	36
Likely Benign	4	0	4
Benign	1	1	2
Total	41	1	42

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap ROPN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →