FREM2

Chr 13AR

FRAS1 related extracellular matrix 2

Also known as: CRYPTOP, FRASRS2

This gene encodes an extracellular matrix protein that maintains skin epithelial integrity, supports epidermal adhesion, and is required for eyelid and anterior eye segment development. Mutations cause Fraser syndrome 2 and isolated cryptophthalmos (absent or malformed eyelids), inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants, indicating its critical developmental role.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.472 OMIM phenotypes
Clinical SummaryFREM2
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.47LOEUF
pLI 0.000
Z-score 6.05
OE 0.36 (0.280.47)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
-0.86Z-score
OE missense 1.06 (1.021.10)
1835 obs / 1734.4 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.36 (0.280.47)
00.351.4
Missense OE1.06 (1.021.10)
00.61.4
Synonymous OE1.07
01.21.6
LoF obs/exp: 38 / 104.8Missense obs/exp: 1835 / 1734.4Syn Z: -1.48
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveFREM2-related Fraser syndromeLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6648th %ile
GOF
0.5465th %ile
LOF
0.3550th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

FREM2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Key Publications
Landmark & review papers · by relevance
PubMed
Fraser Syndrome.
Saleem AA et al.·J Coll Physicians Surg Pak
2015Case report
Cryptophthalmos: associated syndromes and genetic disorders.
Landau-Prat D et al.·Ophthalmic Genet
2023
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC