INSL4

Chr 9

insulin like 4

Also known as: EPIL, PLACENTIN

NCBI Gene: 3641 ENSG00000120211 UniProt: Q14641 OMIM: 600910

The insulin-like 4 protein functions in trophoblast development during early placental formation and regulates bone formation. No established disease associations have been reported for INSL4 mutations in current medical literature. This gene shows very low constraint against loss-of-function variants, suggesting that complete loss of function may be tolerated.

OMIM ResearchSummary from RefSeq, UniProt

INSL4 encodes the insulin-like 4 protein, a member of the insulin superfamily. INSL4 encodes a precursor that undergoes post-translational cleavage to produce 3 polypeptide chains, A-C, that form tertiary structures composed of either all three chains, or just the A and B chains. Expression of INSL4 products occurs within the early placental cytotrophoblast and syncytiotrophoblast. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.93

Clinical Summary— INSL4

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

34 VUS of 40 total submissions

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?

1.93LOEUF

pLI 0.000

Z-score -0.86

OE 1.51 (0.71–1.93)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.43Z-score

OE missense 1.46 (1.25–1.71)

112 obs / 76.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.51 (0.71–1.93)

0≤0.351.4

Missense OE?1.46 (1.25–1.71)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 5 / 3.3Missense obs/exp: 112 / 76.7Syn Z: -0.21

This gene — mechanism propensity

0.6745th %ile

GOF

0.4776th %ile

LOF

0.3357th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

40 submitted variants in ClinVar

ClinVar

Classification Summary

VUS34

Likely Benign4

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	34	0	34
Likely Benign	4	0	4
Benign	1	1	2
Total	39	1	40

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

View in ClinVar →

164 pathogenic / likely-pathogenic (of 177) ClinVar copy-number / structural variants overlap INSL4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →