FREM1

Chr 9ARAD

FRAS1 related extracellular matrix 1

NCBI Gene: 158326ENSG00000164946UniProt: Q5H8C1

Extracellular matrix protein that plays a role in epidermal differentiation and is required for epidermal adhesion during embryonic development

Primary Disease Associations & Inheritance

Bifid nose with or without anorectal and renal anomaliesMIM #608980
AR
Manitoba oculotrichoanal syndromeMIM #248450
AR
Trigonocephaly 2MIM #614485
AD
UniProtBifid nose, with or without anorectal and renal anomalies
1617
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— FREM1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
1617 total variants — no pathogenic classifications of 1617 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.
1.12LOEUF
pLI 0.000
Z-score 0.61
OE 0.93 (0.78–1.12)
Tolerant

Highly tolerant — LoF variants common in population

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.
-3.51Z-score
OE missense 1.29 (1.24–1.35)
1485 obs / 1149.9 exp
Tolerant

Tolerant to missense variation

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.0.93 (0.78–1.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.29 (1.24–1.35)
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.1.30
0≤1.21.6
LoF obs/exp: 83 / 89.2Missense obs/exp: 1485 / 1149.9Syn Z: -5.00

ClinVar Variant Classifications

1617 submitted variants in ClinVar

ClinVar

Classification Summary

Protein Context — Lollipop Plot

FREM1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

FREM1-related Manitoba oculotrichoanal syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Bifid nose with or without anorectal and renal anomalies

MIM #608980

Molecular basis of disorder known

Autosomal recessive

Manitoba oculotrichoanal syndrome

MIM #248450

Molecular basis of disorder known

Autosomal recessive

Trigonocephaly 2

MIM #614485

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Potential Role of FREM1 and Its Isoform TILRR in HIV-1 Acquisition through Mediating Inflammation.
Kashem MA et al.·Int J Mol Sci
2021Review
Novel FREM1 mutations in a patient with MOTA syndrome: Clinical findings, mutation update and review of FREM1-related disorders literature.
Chacon-Camacho OF et al.·Eur J Med Genet
2017Review
Cryptophthalmos: associated syndromes and genetic disorders.
Landau-Prat D et al.·Ophthalmic Genet
2023
Using a new analytic approach for genotyping and phenotyping chromosome 9p deletion syndrome.
Starosta RT et al.·Eur J Hum Genet
2024
Variants in FREM1 and trisomy 18 identified in a neonatal progeria patient.
Siddiqi S et al.·Mol Biol Rep
2023
Overlapping and divergent localization of Frem1 and Fras1 and its functional implications during mouse embryonic development.
Petrou P et al.·Exp Cell Res
2007Functional
Elevated expression of FREM1 in breast cancer indicates favorable prognosis and high-level immune infiltration status.
Li HN et al.·Cancer Med
2020
Development of monoclonal antibodies to interrogate functional domains and isoforms of FREM1 protein.
Yuan XY et al.·Monoclon Antib Immunodiagn Immunother
2014Functional
Two novel mutations within FREM1 gene in patients with bifid nose.
Chen X et al.·BMC Pediatr
2023Cohort
GWAS reveals loci associated with velopharyngeal dysfunction.
Chernus J et al.·Sci Rep
2018
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