ITFG2

protein-coding

integrin alpha FG-GAP repeat containing 2, the group of KICSTOR complex

Gene summary

Involved in cellular response to amino acid starvation; cellular response to glucose starvation; and negative regulation of TORC1 signaling. Located in lysosomal membrane. Part of KICSTOR complex. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

FGGAP1

MANE transcript

NM_018463.4

Inheritance

ClinVar variants

P:2U:83B:2

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr12:2,812,622-2,859,791

External References & Databases

Ensembl (ENSG00000111203)

Transcript & Mutation Effects

hg38 • Region Span ~47.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published PMID: 33083013– Reports four consanguineous families with NDD/ID ± seizures/regression/ataxia and homozygous LoF ITFG2 variants: index family c.361C>T (p.Gln121Ter) with an affected sibling and parental carrier confirmation; plus three additional unrelated cases with c.848-1G>A, c.704dupC (p.Ala236fs), and c.1000_1001delAT (p.Ile334fs). Case-level (biallelic predicted null in AR model; homozygous scored once per family; all consanguineous so −0.5 applied) = 4 families × (1.5 − 0.5) = 4.0; segregation (affected sib counted as segregation + parental carrier confirmation; conservative) = 1.0; case-control = 0; PMID: 33083013 total = 5.0. PMID: 28397838– Reports a consanguineous family with AR intellectual disability and a homozygous stopgain in ITFG2 (reported as a candidate ARID gene in their cohort). Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity present → −0.5) = 1.0; segregation = 0 (not scored here because the paper-level segregation specifics for the ITFG2 family are not extracted in our log yet); case-control = 0; PMID: 28397838 total = 1.0. PMID: 33875846– Reports three consanguineous families with ITFG2 homozygous LoF variants (c.361C>T, c.704dup, c.848-1G>A). These appear to overlap with families already described in PMID:33083013, so no additional points are added to avoid double counting; retained as supportive replication/secondary report. PMID: 33875846 total = 0. Published genetic evidence total = (5.0 + 1.0 + 0) = 6.0/12 Genetic evidence – Our cases Family 1– One proband (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5) = 1.0; segregation = 0; case-control = 0; Family 1 total = 1.0. Our cases total = 1.0/12 Total genetic evidence (published + our cases) 6.0 + 1.0 = 7.0/12 Experimental evidence – Published PMID: 28199306 (Wolfson et al., 2017) – Defines KICSTOR, a complex including ITFG2, required for nutrient deprivation to inhibit mTORC1 signaling and recruiting inhibitory machinery to lysosomes; supports biological plausibility for an mTOR-pathway NDD/epilepsy mechanism. Functional alteration in engineered cells / pathway evidence supporting LoF mechanism = 1.0; PMID: 28199306 experimental total = 1.0. Experimental evidence total = 1.0/6 Overall score = 7.0 + 1.0 = 8.0/18 Overall score = 8.0

neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITFG2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 78

not providedTotal: 3

Neurodevelopmental disorderTotal: 1

ITFG2-associated disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018463.4. 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						0
missense		1 clinvar	77 clinvar	2 clinvar		80
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)		1 clinvar	4 clinvar			5
Total	0	2	83	2	0	87

Highest pathogenic variant AF is 0.000008063115

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 68 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018463.4	RefSeq	NP_060933.3	12	MANE Select
ENST00000228799.7	Ensembl	ENSP00000228799.2	12	MANE Select
ENST00000534935.5	Ensembl	ENSP00000439324.1	3	Standard
ENST00000537851.5	Ensembl	ENSP00000445769.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

germinal center B cell differentiation
cellular response to amino acid starvation
cellular response to glucose starvation
negative regulation of TORC1 signaling

Cellular Component

nucleoplasm
lysosomal membrane
cytosol
KICSTOR complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000228799
Coding exons: 12
Length: 47170
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 51
Defined: 125747
p: 0.000203

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.801	233	270	0.863	0.0000156	2904
Missense (PolyPhen)		68	87.173	0.78006		930
Synonymous	0.831	97	108	0.898	0.00000629	893
Loss of Function	1.75	16	25.5	0.626	0.00000136	268

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00083	0.00082	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00022	0.00021	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

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}.;

Recessive Scores

pRec: 0.0891

Intolerance Scores

LoFtool: 0.492
RVIS EVS: -0.82
RVIS percentile EVS: 11.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.943

Gene Damage Prediction

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