NTHL1

Chr 16AR

nth like DNA glycosylase 1

Also known as: FAP3, NTH1, OCTS3, hNTH1

NCBI Gene: 4913ENSG00000065057UniProt: P78549

The protein encoded by this gene is a DNA N-glycosylase of the endonuclease III family. Like a similar protein in E. coli, the encoded protein has DNA glycosylase activity on DNA substrates containing oxidized pyrimidine residues and has apurinic/apyrimidinic lyase activity. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

Familial adenomatous polyposis 3MIM #616415
AR
596
ClinVar variants
99
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— NTHL1
🧬
Gene-Disease Validity (ClinGen)
NTHL1-deficiency tumor predisposition syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
99 Pathogenic / Likely Pathogenic· 346 VUS of 596 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.59LOEUF
pLI 0.000
Z-score -0.10
OE 1.03 (0.68–1.59)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.80Z-score
OE missense 1.16 (1.04–1.29)
233 obs / 201.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.03 (0.68–1.59)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.16 (1.04–1.29)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 14 / 13.6Missense obs/exp: 233 / 201.2Syn Z: 0.41

ClinVar Variant Classifications

596 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic75
Likely Pathogenic24
VUS346
Likely Benign138
Conflicting13
75
Pathogenic
24
Likely Pathogenic
346
VUS
138
Likely Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
46
0
29
0
75
Likely Pathogenic
15
0
9
0
24
VUS
3
284
57
2
346
Likely Benign
1
6
81
50
138
Benign
0
0
0
0
0
Conflicting
—13
Total6529017652596

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

View in ClinVar →

Protein Context — Lollipop Plot

NTHL1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NTHL1-related adenomatous polyposis, colorectal cancer, breast cancer and other tumours

definitive
ARLoss Of FunctionAbsent Gene Product
Cancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Familial adenomatous polyposis 3

MIM #616415

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NTHL1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test?
Rebuzzi F et al.·Int J Mol Sci
2023Review
Genetics, genomics and clinical features of adenomatous polyposis.
Joo JE et al.·Fam Cancer
2025Review
POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes.
Magrin L et al.·Oncogene
2021Review
Intestinal and extraintestinal neoplasms in patients with NTHL1 tumor syndrome: a systematic review.
Beck SH et al.·Fam Cancer
2022Review
Genotype-phenotype correlations in NTHL1-associated tumour syndrome: case report and literature review.
Bukowska A et al.·Swiss Med Wkly
2025Review
NTHL1 and MUTYH polyposis syndromes: two sides of the same coin?
Weren RD et al.·J Pathol
2018Review
Germline pathogenic variants in prostate cancer.
Shakroo YM et al.·Pathol Res Pract
2024
Genomic landscape of colorectal carcinogenesis.
Kim JC et al.·J Cancer Res Clin Oncol
2022Review
NTHL1 is a recessive cancer susceptibility gene.
Nurmi AK et al.·Sci Rep
2023
Concurrent Reduced Expression of Contiguous PKD1, TSC2 and NTHL1 Leading to Kidney Diseases and Multiple Diverse Renal Cancers.
Meguro S et al.·Cancer Genomics Proteomics
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Familial Adenomatous Polyposis (FAP)Attenuated Familial Adenomatous Polyposis (AFAP)MUTYH-Associated Polyposis (MAP)

Familial Adenomatous Poliposys Italian Network (Rete Italiana Poliposi Adenomatosa Familiare)

ACTIVE NOT RECRUITING
NCT07461246Fondazione IRCCS Istituto Nazionale dei Tumori, MilanoStarted 2024-05-13

External Resources

Links to major genomics databases and tools