KREMEN1

Chr 22AR

kringle containing transmembrane protein 1

Also known as: ECTD13, KREMEN, KRM1

NCBI Gene: 83999ENSG00000183762UniProt: Q96MU8

This gene encodes a high-affinity dickkopf homolog 1 (DKK1) transmembrane receptor that functionally cooperates with DKK1 to block wingless (WNT)/beta-catenin signaling. The encoded protein is a component of a membrane complex that modulates canonical WNT signaling through lipoprotein receptor-related protein 6 (LRP6). It contains extracellular kringle, WSC, and CUB domains. Mutations in this gene result in ectodermal dysplasia. This protein has also been found to be a functional receptor for Coxsackievirus A10 and may be an alternative entry receptor for SARS-CoV-2. [provided by RefSeq, Nov 2021]

Primary Disease Associations & Inheritance

Ectodermal dysplasia 13, hair/tooth typeMIM #617392
AR
170
ClinVar variants
29
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— KREMEN1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
29 Pathogenic / Likely Pathogenic· 89 VUS of 170 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.64LOEUF
pLI 0.011
Z-score 2.76
OE 0.34 (0.19–0.64)
Tolerant

Typical tolerance to LoF variation

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.
0.78Z-score
OE missense 0.87 (0.78–0.97)
239 obs / 275.3 exp
Tolerant

Mild missense constraint

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.0.34 (0.19–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.78–0.97)
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.0.91
0≤1.21.6
LoF obs/exp: 7 / 20.5Missense obs/exp: 239 / 275.3Syn Z: 0.70

ClinVar Variant Classifications

170 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic1
VUS89
Likely Benign26
Benign14
Conflicting1
28
Pathogenic
1
Likely Pathogenic
89
VUS
26
Likely Benign
14
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
26
0
28
Likely Pathogenic
0
0
1
0
1
VUS
4
82
3
0
89
Likely Benign
0
7
7
12
26
Benign
0
4
2
8
14
Conflicting
—1
Total5943920159

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

View in ClinVar →

Protein Context — Lollipop Plot

KREMEN1 · 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

Ectodermal dysplasia 13, hair/tooth type

MIM #617392

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Receptome profiling identifies KREMEN1 and ASGR1 as alternative functional receptors of SARS-CoV-2.
Gu Y et al.·Cell Res
2022Functional
ACE2-Independent Alternative Receptors for SARS-CoV-2.
Lim S et al.·Viruses
2022Review
KREMEN1 Variants Associated with Ectodermal Dysplasia Impair Complex Formation of KREMEN1 with DKK1 and LRP6 and Attenuate WNT3A Response.
Rosen N et al.·J Invest Dermatol
2026
KREMEN1 Is a Host Entry Receptor for a Major Group of Enteroviruses.
Staring J et al.·Cell Host Microbe
2018
Tooth agenesis: What do we know and is there a connection to cancer?
Bonczek O et al.·Clin Genet
2021Review
Genetic analysis: Wnt and other pathways in nonsyndromic tooth agenesis.
Yu M et al.·Oral Dis
2019Review
Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families.
Issa YA et al.·Eur J Hum Genet
2016
Predicting human and viral protein variants affecting COVID-19 susceptibility and repurposing therapeutics.
Waman VP et al.·Sci Rep
2024
Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis.
Dinckan N et al.·J Dent Res
2018
Genetic association study of KREMEN1 and DKK1 and schizophrenia in a Japanese population.
Aleksic B et al.·Schizophr Res
2010
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