KPTN

Chr 19AR

kaptin, actin binding protein

Also known as: 2E4, KICS4, MRT41

NCBI Gene: 11133ENSG00000118162UniProt: Q9Y664

This gene encodes a filamentous-actin-associated protein, which is involved in actin dynamics and plays an important role in neuromorphogenesis. This protein is part of the KICSTOR protein complex that localizes to lysosomes. Mutations in this gene result in an autosomal recessive form of intellectual disability. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 41MIM #615637
AR
235
ClinVar variants
33
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— KPTN
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 115 VUS of 235 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.81LOEUF
pLI 0.000
Z-score 2.28
OE 0.50 (0.32–0.81)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.45Z-score
OE missense 0.75 (0.67–0.84)
200 obs / 266.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.50 (0.32–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.67–0.84)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 12 / 24.0Missense obs/exp: 200 / 266.4Syn Z: 0.83

ClinVar Variant Classifications

235 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic11
VUS115
Likely Benign61
Benign17
Conflicting9
22
Pathogenic
11
Likely Pathogenic
115
VUS
61
Likely Benign
17
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
13
0
22
Likely Pathogenic
6
1
4
0
11
VUS
4
97
13
1
115
Likely Benign
0
4
23
34
61
Benign
0
1
10
6
17
Conflicting
—9
Total191036341235

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

View in ClinVar →

Protein Context — Lollipop Plot

KPTN · protein map & ClinVar variants

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

Gene2Phenotype Curations

KPTN-related macrocephaly, neurodevelopmental delay, and seizures

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
KAPTIN; KPTN
MIM #615620 · *

Intellectual developmental disorder, autosomal recessive 41

MIM #615637

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — KPTN
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathogenic variants in KPTN gene identified by clinical whole-genome sequencing.
Thiffault I et al.·Cold Spring Harb Mol Case Stud
2020Case report
Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes.
Levitin MO et al.·Brain
2023Functional
Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.
Buchert R et al.·Am J Hum Genet
2025
Clinical and genetic characterization of patients segregating variants in KPTN, MINPP1, NGLY1, AP4B1, and SON underlying neurodevelopmental disorders: Genetic and phenotypic expansion.
Ullah A et al.·Int J Dev Neurosci
2022Cohort
Nonsense variant in a consanguineous family expands the phenotype of KPTN gene-related syndrome to include hearing impairment.
Liaqat K et al.·Clin Genet
2023Case report
Pathogenic variants in KPTN, a rare cause of macrocephaly and intellectual disability.
Pacio Miguez M et al.·Am J Med Genet A
2020
Duplication at 19q13.32q13.33 Segregating with Neuropsychiatric Phenotype in a Three-Generation Family: Towards the Definition of a Critical Region.
Guadagnolo D et al.·Genes (Basel)
2023Review
KPTN gene homozygous variant-related syndrome in the northeast of Brazil: A case report.
Lucena PH et al.·Am J Med Genet A
2020Case report
Array-CGH detection of a de novo 0.8Mb deletion in 19q13.32 associated with mental retardation, cardiac malformation, cleft lip and palate, hearing loss and multiple dysmorphic features.
Leal T et al.·Eur J Med Genet
2009Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools