KPTN

protein-coding

kaptin, actin binding protein, the group of KICSTOR complex

Gene summary

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]

MANE transcript

NM_007059.4

Inheritance

ClinVar variants

P:29U:112B:50

Top phenotype

Intellectual developmental disorder, autosomal recessive 41

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr19:47,475,150-47,484,265

External References & Databases

Ensembl (ENSG00000118162)

Transcript & Mutation Effects

hg38 • Region Span ~9.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: ClinGen

*KPTN* encodes a component of the mTOR regulatory complex KICSTOR. *KPTN* was first reported in relation to autosomal recessive complex neurodevelopmental disorder in 2014 (Baple et al., PMID: 24239382). The disorder is characterized by global developmental delay, intellectual disability, hypotonia, macrocephaly with frontal bossing, and facial dysmorphic features. Additionally, more variable features can include seizures, anxiety, and autistic features. Six variants (2 frameshift, 2 splice, 1 nonsense, and 1 inframe insertion) that have been reported in 9 probands in 6 publications (PMIDs: 24239382, 25847626, 31999056, 32358097, 32808430, 36703628) are included in this curation. Variants in this gene segregated with disease in 11 additional family members. Nine affected individuals belong to 4 nuclear families from a single extended Amish pedigree; all are homozygous or compound heterozygous for two founder variants (p.Ser259* and p.Met241_Gln246dup) (PMID: 24239382). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by functional alterations in non-patient cells, and a *Kptn* null mouse model that exhibits cognitive deficits, macrocephaly, and increased mTOR signalling (PMID: 37437211). In summary, there is definitive evidence supporting the relationship between *KPTN* and autosomal recessive complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 16, 2025 (SOP Version 11).

macrocephaly-developmental delay syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014289

Submitter: Orphanet

macrocephaly-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014289

Submitter: G2P

macrocephaly-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014289

Submitter: PanelApp Australia

macrocephaly-developmental delay syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014289

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 41AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24239382

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KPTN variants in ClinVar

6 Conditions Cataloged

Macrocephaly-developmental delay syndromeTotal: 142

Inborn genetic diseasesTotal: 75

not providedTotal: 49

not specifiedTotal: 24

KPTN-related disorderTotal: 21

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007059.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	37 clinvar	3 clinvar	42
missense		3 clinvar	102 clinvar	10 clinvar		115
nonsense	2 clinvar	4 clinvar	1 clinvar			7
start loss						0
frameshift	7 clinvar	4 clinvar	3 clinvar			14
splice donor/acceptor (+/-2bp)	4 clinvar	5 clinvar	4 clinvar			13
Total	13	16	112	47	3	191

Highest pathogenic variant AF is 0.0006136163

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007059.4	RefSeq	NP_008990.2	12	MANE Select
ENST00000338134.8	Ensembl	ENSP00000337850.2	12	MANE Select
NM_001291296.2	RefSeq	NP_001278225.1	10	Standard
ENST00000594208.5	Ensembl	ENSP00000470364.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

actin filament organization
cellular response to amino acid starvation
cellular response to glucose starvation
protein localization to lysosome
negative regulation of TORC1 signaling

Molecular Function

actin filament binding

Cellular Component

lysosomal membrane
lamellipodium
filamentous actin
stereocilium
postsynaptic actin cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338134
Coding exons: 12
Length: 9125
Individuals with no LoFs: 124726
Homozygous LoFs: 0
Heterozygous LoFs: 84
Defined: 124810
p: 0.000337

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.45	200	266	0.751	0.0000154	2776
Missense (PolyPhen)		68	90.477	0.75157		1016
Synonymous	0.829	106	117	0.903	0.00000703	902
Loss of Function	2.28	12	24.0	0.499	0.00000122	248

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00034	0.00032	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00031	0.00028	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.00052	0.00052	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex is also probably involved in the regulation of mTORC1 by glucose. {ECO:0000269|PubMed:28199306}.;
Disease: DISEASE: Mental retardation, autosomal recessive 41 (MRT41) [MIM:615637]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT41 most consistent features are global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and some features suggestive of a pervasive developmental disorder. Less common features include fifth finger clinodactyly, recurrent pneumonia, and hepatosplenomegaly. {ECO:0000269|PubMed:24239382}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.441
RVIS EVS: -0.47
RVIS percentile EVS: 23.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.966

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium