ZNHIT2

Chr 11

zinc finger HIT-type containing 2

Also known as: C11orf5, FON

NCBI Gene: 741 ENSG00000174276 UniProt: Q9UHR6 OMIM: 604575

The ZNHIT2 protein acts as a bridging factor that mediates interactions between the R2TP/Prefoldin-like complex and U5 small nuclear ribonucleoprotein, playing a role in regulating U5 snRNP complex composition. Mutations in ZNHIT2 cause autosomal recessive spinal muscular atrophy with pontocerebellar hypoplasia, affecting the neuromuscular and central nervous systems. The gene shows tolerance to loss-of-function variation (pLI near zero), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable zinc ion binding activity. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.43

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.43LOEUF

pLI 0.000

Z-score 0.59

OE 0.80 (0.47–1.43)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.03Z-score

OE missense 1.01 (0.90–1.12)

224 obs / 222.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.80 (0.47–1.43)

0≤0.351.4

Missense OE?1.01 (0.90–1.12)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 8 / 10.0Missense obs/exp: 224 / 222.8Syn Z: -1.56

Background carrier burden — how many people carry a rare variant somewhere in ZNHIT2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 82

686 rare PASS variants

Rare truncating (LoF)

1 in 1,900

95 rare PASS variants

Rare synonymous (reference)

1 in 110

359 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ZNHIT2. 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 120	1 in 1,900
South Asian	~43k	1 in 85	1 in 2,600
Remaining (unassigned)	~30k	1 in 52	1 in 2,800
European (Finnish)	~27k	1 in 230	1 in 2,400
Admixed American	~22k	1 in 82	1 in 1,300
African / African American	~21k	1 in 98	1 in 1,700
East Asian	~20k	1 in 120	1 in 1,600
Ashkenazi Jewish	~13k	1 in 200	≈ 1 in 5,800
Middle Eastern	~2,884	1 in 65	≈ 1 in 930

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): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓