INSL6

Chr 9

insulin like 6

Also known as: RIF1

The protein encoded by INSL6 belongs to the insulin superfamily and may function in sperm development and fertilization, with expression restricted to testicular interstitial cells. Mutations in INSL6 cause autosomal recessive cryptorchidism with or without insulin-like factor 6 deficiency, affecting male reproductive development. The gene shows very low constraint against loss-of-function variants.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 1.92
Clinical SummaryINSL6
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
83 unique Pathogenic / Likely Pathogenic· 67 VUS of 199 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
1.92LOEUF
pLI 0.000
Z-score -1.11
OE 1.43 (0.881.92)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-2.45Z-score
OE missense 1.62 (1.441.82)
201 obs / 124.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE1.43 (0.881.92)
00.351.4
Missense OE1.62 (1.441.82)
00.61.4
Synonymous OE1.59
01.21.6
LoF obs/exp: 11 / 7.7Missense obs/exp: 201 / 124.1Syn Z: -3.20
DN
0.79top 25%
GOF
0.2895th %ile
LOF
0.3453th %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

199 submitted variants in ClinVar

Classification Summary

Pathogenic77
Likely Pathogenic6
VUS67
Likely Benign34
Benign10
Conflicting3
77
Pathogenic
6
Likely Pathogenic
67
VUS
34
Likely Benign
10
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
77
0
77
Likely Pathogenic
0
1
5
0
6
VUS
5
55
6
1
67
Likely Benign
0
1
12
21
34
Benign
0
1
4
5
10
Conflicting
3
Total55810427197

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

View in ClinVar →

Protein Context — Lollipop Plot

INSL6 · 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
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