MORC1

Chr 3

MORC family CW-type zinc finger 1

Also known as: CT33, MORC, ZCW6

NCBI Gene: 27136 ENSG00000114487 UniProt: Q86VD1 OMIM: 603205

The protein is required for spermatogenesis and is essential for de novo DNA methylation and silencing of transposable elements in male embryonic germ cells. Mutations in MORC1 cause male infertility with no other apparent clinical phenotype. The gene shows extremely high constraint against loss-of-function variants (pLI near 1.0), suggesting that mutations may have significant biological impact despite the testis-specific expression pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes the human homolog of mouse morc and like the mouse protein it is testis-specific. Mouse studies support a testis-specific function since only male knockout mice are infertile; infertility is the only apparent defect. These studies further support a role for this protein early in spermatogenesis, possibly by affecting entry into apoptosis because testis from knockout mice show greatly increased numbers of apoptotic cells. [provided by RefSeq, Jan 2009]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.51

Clinical Summary— MORC1

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.

📋

ClinVar Variants

89 VUS of 114 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.000

Z-score 4.59

OE 0.35 (0.24–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.45Z-score

OE missense 0.81 (0.75–0.89)

395 obs / 485.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.24–0.51)

0≤0.351.4

Missense OE?0.81 (0.75–0.89)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 20 / 57.5Missense obs/exp: 395 / 485.1Syn Z: -0.09

This gene — mechanism propensity

0.6552th %ile

GOF

0.5759th %ile

LOF

0.3357th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

114 submitted variants in ClinVar

ClinVar

Classification Summary

VUS89

Likely Benign11

Benign3

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	88	1	0	89
Likely Benign	8	0	3	11
Benign	1	0	2	3
Total	97	1	5	103

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap MORC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →