NFATC2IP

Chr 16

nuclear factor of activated T cells 2 interacting protein

Also known as: ESC2, NIP45, RAD60

NCBI Gene: 84901 ENSG00000176953 UniProt: Q8NCF5 OMIM: 614525

This protein regulates NFAT-driven transcription of specific cytokine genes including IL4, IL5, and IL13 in T-helper 2 cells by recruiting PRMT1 to promote histone methylation and acetylation. Mutations cause autosomal recessive primary immunodeficiency with defective T-helper cell cytokine production, resulting in recurrent infections and immune dysregulation typically presenting in early childhood. The gene shows tolerance to loss-of-function variants, consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.02

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.02LOEUF

pLI 0.000

Z-score 1.51

OE 0.60 (0.37–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.64Z-score

OE missense 0.88 (0.78–0.99)

190 obs / 216.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.37–1.02)

0≤0.351.4

Missense OE?0.88 (0.78–0.99)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 10 / 16.7Missense obs/exp: 190 / 216.5Syn Z: 1.42

Background carrier burden — how many people carry a rare variant somewhere in NFATC2IP?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

592 rare PASS variants

Rare truncating (LoF)

1 in 1,400

93 rare PASS variants

Rare synonymous (reference)

1 in 250

256 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NFATC2IP. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 180	1 in 1,700
South Asian	~43k	1 in 100	1 in 830
Remaining (unassigned)	~30k	1 in 120	1 in 2,700
European (Finnish)	~27k	1 in 240	1 in 3,800
Admixed American	~22k	1 in 150	1 in 1,400
African / African American	~21k	1 in 120	1 in 1,200
East Asian	~20k	1 in 200	1 in 3,700
Ashkenazi Jewish	~13k	≈ 1 in 3,400	≈ 1 in 10,000
Middle Eastern	~2,884	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 8 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 8.? see exons ↓