HSPH1

Chr 13

heat shock protein family H (Hsp110) member 1

Also known as: HSP105, HSP105A, HSP105B, NY-CO-25

NCBI Gene: 10808 ENSG00000120694 UniProt: Q92598

The protein functions as a nucleotide exchange factor for heat shock protein 70 family chaperones and acts as a holdase that prevents aggregation of misfolded proteins under cellular stress conditions. Mutations cause neurodevelopmental disorder with spastic diplegia and visual defects, typically presenting in early childhood with developmental delays, spasticity affecting the legs, and ophthalmologic abnormalities. The gene is highly constrained against loss-of-function variants and inheritance follows an autosomal dominant pattern.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the heat shock protein 70 family of proteins. The encoded protein functions as a nucleotide exchange factor for the molecular chaperone heat shock cognate 71 kDa protein (Hsc70). In addition, this protein plays a distinct but related role as a holdase that inhibits the aggregation of misfolded proteins, including the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Elevated expression of this protein has been observed in numerous human cancers. [provided by RefSeq, Mar 2017]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

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P/LP missense

0.26

LOEUF· LoF intol.

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Mechanism

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.998

Z-score 5.38

OE 0.13 (0.07–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.72Z-score

OE missense 0.77 (0.70–0.84)

344 obs / 446.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.26)

0≤0.351.4

Missense OE?0.77 (0.70–0.84)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 6 / 44.9Missense obs/exp: 344 / 446.2Syn Z: -1.36

Background carrier burden — how many people carry a rare variant somewhere in HSPH1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 62

1,024 rare PASS variants

Rare truncating (LoF)

1 in 1,300

104 rare PASS variants

Rare synonymous (reference)

1 in 93

451 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HSPH1. 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 79	1 in 2,900
South Asian	~43k	1 in 63	1 in 1,200
Remaining (unassigned)	~30k	1 in 48	1 in 1,100
European (Finnish)	~27k	1 in 200	1 in 2,000
Admixed American	~22k	1 in 68	1 in 690
African / African American	~21k	1 in 56	1 in 1,200
East Asian	~20k	1 in 110	1 in 590
Ashkenazi Jewish	~13k	1 in 320	none seen
Middle Eastern	~2,884	1 in 110	≈ 1 in 2,900

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): 16 of 18 coding exons well covered in gnomAD exomes; exons 2, 9 marginal. Genomes: all 18.? see exons ↓