LORICRIN

Chr 1AD

loricrin cornified envelope precursor protein

Also known as: LOR

NCBI Gene: 4014 ENSG00000203782 UniProt: P23490 OMIM: 152445

This gene encodes loricrin, a major protein component of the cornified cell envelope found in terminally differentiated epidermal cells. Mutations in this gene are associated with Vohwinkel's syndrome and progressive symmetric erythrokeratoderma, both inherited skin diseases. [provided by RefSeq, Jul 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.081 OMIM phenotype

Clinical Summary— LORICRIN

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

8 unique Pathogenic / Likely Pathogenic· 96 VUS of 142 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.08LOEUF

pLI 0.335

Z-score 1.49

OE 0.23 (0.08–1.08)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.87Z-score

OE missense 1.23 (1.07–1.41)

141 obs / 114.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.23 (0.08–1.08)

0≤0.351.4

Missense OE?1.23 (1.07–1.41)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 1 / 4.4Missense obs/exp: 141 / 114.7Syn Z: -0.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveLORICRIN-related palmoplantar keratoderma Vohwinkel syndrome with ichthyosisOTHERAD

This gene — mechanism propensity

0.7227th %ile

GOF

0.85top 5%

LOF

0.2971th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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

142 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic4

VUS96

Likely Benign18

Benign15

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	0	0	0	4
Likely Pathogenic	3	1	0	0	4
VUS	3	91	1	1	96
Likely Benign	0	8	0	10	18
Benign	0	9	1	5	15
Conflicting	—				5
Total	10	109	2	16	142

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap LORICRIN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →