FITM2

Chr 20AR

fat storage inducing transmembrane protein 2

Also known as: C20orf142, Fit2, SIDDIS, dJ881L22.2

NCBI Gene: 128486 ENSG00000197296 UniProt: Q8N6M3 OMIM: 612029

The protein functions as a fatty acyl-coenzyme A diphosphatase in the endoplasmic reticulum, hydrolyzing fatty acyl-CoA substrates and maintaining ER structure and lipid droplet biogenesis for cellular lipid and energy homeostasis. Mutations cause Siddiqi syndrome, inherited in an autosomal recessive pattern. The gene shows low constraint to loss-of-function variation, consistent with recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables coenzyme A diphosphatase activity. Involved in several processes, including fatty-acyl-CoA catabolic process; lipid droplet formation; and lipid homeostasis. Predicted to be located in endoplasmic reticulum and membrane. Predicted to be active in endoplasmic reticulum membrane. Implicated in Siddiqi syndrome. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.551 OMIM phenotype

Clinical Summary— FITM2

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Gene-Disease Validity (ClinGen)

Siddiqi syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 35 VUS of 65 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.55LOEUF

pLI 0.000

Z-score 0.29

OE 0.90 (0.54–1.55)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.60Z-score

OE missense 0.86 (0.74–1.00)

122 obs / 142.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.90 (0.54–1.55)

0≤0.351.4

Missense OE?0.86 (0.74–1.00)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 9 / 10.0Missense obs/exp: 122 / 142.0Syn Z: -0.72

This gene — mechanism propensity

0.6454th %ile

GOF

0.5660th %ile

LOF

0.2970th %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

65 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic6

VUS35

Likely Benign13

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	0	0	5
Likely Pathogenic	4	2	0	0	6
VUS	0	34	1	0	35
Likely Benign	0	5	2	6	13
Benign	0	0	3	0	3
Conflicting	—				1
Total	9	41	6	6	63

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap FITM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →