FREM2

Chr 13

FRAS1 related extracellular matrix 2

Also known as: CRYPTOP, FRASRS2

NCBI Gene: 341640 ENSG00000150893 UniProt: Q5SZK8

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.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an integral membrane protein containing numerous CSPG (chondroitin sulfate proteoglycan element) repeats and Calx-beta domains. The encoded protein localizes to the basement membrane, forming a ternary complex that plays a role in epidermal-dermal interactions. This protein is important for the integrity of skin and renal epithelia. Mutations in this gene are associated with Fraser syndrome. [provided by RefSeq, Apr 2014]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtFraser syndrome 2

UniProtCryptophthalmos, unilateral or bilateral, isolated

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.47

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — FREM2

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.000

Z-score 6.05

OE 0.36 (0.28–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.86Z-score

OE missense 1.06 (1.02–1.10)

1835 obs / 1734.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.36 (0.28–0.47)

0≤0.351.4

Missense OE?1.06 (1.02–1.10)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 38 / 104.8Missense obs/exp: 1835 / 1734.4Syn Z: -1.48

Background carrier burden — how many people carry a rare variant somewhere in FREM2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 13

4,325 rare PASS variants

Rare truncating (LoF)

1 in 590

337 rare PASS variants

Rare synonymous (reference)

1 in 28

1,663 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FREM2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 20	1 in 550
South Asian	~43k	1 in 12	1 in 660
Remaining (unassigned)	~30k	1 in 11	1 in 770
European (Finnish)	~27k	1 in 50	1 in 1,700
Admixed American	~22k	1 in 12	1 in 530
African / African American	~21k	1 in 13	1 in 530
East Asian	~20k	1 in 14	1 in 730
Ashkenazi Jewish	~13k	1 in 75	1 in 2,600
Middle Eastern	~2,884	1 in 12	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 22 of 24 coding exons well covered in gnomAD exomes; exons 2, 3 marginal. Genomes: all 24.? see exons ↓