FITM2

protein-coding

fat storage inducing transmembrane protein 2

Gene summary

Enables coenzyme A diphosphatase activity. Involved in fatty-acyl-CoA catabolic process; lipid droplet formation; and lipid homeostasis. Predicted to be active in endoplasmic reticulum membrane. Implicated in Siddiqi syndrome. [provided by Alliance of Genome Resources, Jun 2026]

Previous symbols:

C20orf142

MANE transcript

NM_001080472.4

Inheritance

ClinVar variants

P:14U:39B:16

Top phenotype

Siddiqi syndrome

gnomAD constraint

pLI —, LoF o/e 0.9

Max pathogenic AF

—

Genomic locus

chr20:44,302,840-44,311,202

External References & Databases

Ensembl (ENSG00000197296)

Transcript & Mutation Effects

hg38 • Region Span ~8.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Siddiqi syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032842

Submitter: ClinGen

The *FITM2* gene is located on chromosome 20 at 20q13.12. It encodes for the fat storage-inducing transmembrane protein 2, embedded in the wall of the endoplasmic reticulum where they regulate lipid droplet formation in the cytosol. *FITM2 *was first reported in relation to autosomal recessive Siddiqi syndrome (SIDDIS) in 2017 (Zazo Seco et al., PMID: 28067622). This disease is caused by homozygous or compound heterozygous mutation in the *FITM2* gene. The associated phenotypes involve the nervous system and musculature including hypotonia, global developmental delay, poor fine motor skills, impaired intellectual development, and sensorineural hearing impairment. More variable features may include ichthyosis-like skin abnormalities or sensory neuropathy. Around 5 unique variants (e.g., nonsense, frameshift, and missense) have been reported in at least 4 probands in various publications (PMID: 28067622, 30214770, 30288795, 35754111). A LOF nonsense variant was also found to segregate with the disorder in additional family members with a LOD score of 4.00 (PMID: 28067622). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by experimental evidence in Drosophila (animal model) where RNAi-induced gene downregulation of *Fitm* gene resulted in severely impaired and uncoordinated locomotion along with sensory neuropathy, thus recapitulating the phenotypic features of Siddiqi syndrome (PMID: 28067622). Symptomatic evidence for dyskinetic cerebral palsy has also been reported in one of the probands (PMID: 30214770). In summary, there is definitive evidence to support the relationship of the *FITM2* gene with Siddiqi syndrome. This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 17/10/2022 (SOP Version 9).

Siddiqi syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032842

Submitter: PanelApp Australia

Siddiqi syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032842

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Siddiqi syndromeAR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: Among other findings, individuals may have prelingual hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 28067622; 30214770; 30288795

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FITM2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 36

not providedTotal: 22

FITM2-related disorderTotal: 15

Siddiqi syndromeTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080472.4. 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			1 clinvar	10 clinvar		11
missense		1 clinvar	38 clinvar	6 clinvar		45
nonsense	4 clinvar	3 clinvar				7
start loss		2 clinvar				2
frameshift	1 clinvar	3 clinvar				4
splice donor/acceptor (+/-2bp)						0
Total	5	9	39	16	0	69

Highest pathogenic variant AF is 0.000013137842

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080472.4	RefSeq	NP_001073941.1	2	MANE Select
ENST00000396825.4	Ensembl	ENSP00000380037.3	2	MANE Select
ENST00001091850.1	Ensembl	ENSP00000761656.1	2	Standard
ENST00001127724.1	Ensembl	ENSP00000797529.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fitm2	Danio rerio	Structure: pancreatic B cell Quality: decreased area abnormal

Gene / Model

Organism

Observed Phenotype

fitm2

Danio rerio

Structure: pancreatic B cell

Quality: decreased area

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of lipids
Metabolism
Lipid particle organization

Biological Process

cytoskeleton organization
phospholipid biosynthetic process
regulation of triglyceride biosynthetic process
positive regulation of sequestering of triglyceride
lipid storage

Molecular Function

molecular_function

Cellular Component

endoplasmic reticulum membrane
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396825
Coding exons: 2
Length: 8332
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125747
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.598	122	142	0.859	0.00000773	1683
Missense (PolyPhen)		40	50.804	0.78735		607
Synonymous	-0.717	73	65.6	1.11	0.00000392	536
Loss of Function	0.291	9	9.99	0.901	5.20e-7	101

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays an important role in lipid droplet accumulation. Plays a role in the regulation of cell morphology and cytoskeletal organization. {ECO:0000269|PubMed:18160536, ECO:0000269|PubMed:21834987}.;

Intolerance Scores

LoFtool: 0.401
RVIS EVS: 0.02
RVIS percentile EVS: 55.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.714

Gene Damage Prediction

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