ITIH5

Chr 10

inter-alpha-trypsin inhibitor heavy chain 5

Also known as: ITI-HC5, PP14776

NCBI Gene: 80760ENSG00000123243UniProt: Q86UX2

The protein encoded by this gene is a heavy chain component of inter-alpha-trypsin inhibitor family members that stabilize the extracellular matrix and inhibit serine proteases, and may function as a tumor suppressor. This gene shows very low constraint against loss-of-function variants (pLI near zero, LOEUF 1.21), suggesting high tolerance to protein loss. No well-established Mendelian diseases have been definitively associated with mutations in this gene in the pediatric population.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
11
Pubs (1 yr)
24
P/LP submissions
0%
P/LP missense
1.21
LOEUF
DN
Mechanism· predicted
Clinical Summary— ITIH5
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
24 unique Pathogenic / Likely Pathogenic· 155 VUS of 222 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
1.21LOEUF
pLI 0.000
Z-score 0.53
OE 0.91 (0.69–1.21)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.14Z-score
OE missense 0.98 (0.92–1.05)
559 obs / 568.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.91 (0.69–1.21)
0≤0.351.4
Missense OE0.98 (0.92–1.05)
0≤0.61.4
Synonymous OE1.16
0≤1.21.6
LoF obs/exp: 33 / 36.4Missense obs/exp: 559 / 568.1Syn Z: -1.99
DN
0.6162th %ile
GOF
0.5072th %ile
LOF
0.4136th %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

222 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic1
VUS155
Likely Benign16
Benign3
23
Pathogenic
1
Likely Pathogenic
155
VUS
16
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
23
0
23
Likely Pathogenic
0
0
1
0
1
VUS
0
143
12
0
155
Likely Benign
0
14
1
1
16
Benign
0
0
1
2
3
Total0157383198

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

View in ClinVar →

Protein Context — Lollipop Plot

ITIH5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients