NTHL1

Chr 16AR

nth like DNA glycosylase 1

Also known as: FAP3, NTH1, OCTS3, hNTH1

NCBI Gene: 4913 ENSG00000065057 UniProt: P78549 OMIM: 602656

NTHL1 encodes a bifunctional DNA N-glycosylase that catalyzes the first step in base excision repair, the primary pathway for repairing oxidative DNA damage, by cleaving damaged pyrimidine bases and associated phosphodiester bonds. Biallelic mutations cause familial adenomatous polyposis 3, characterized by the development of multiple colorectal adenomas that can progress to colorectal cancer. This condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.591 OMIM phenotype

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

174 unique Pathogenic / Likely Pathogenic· 967 VUS of 1830 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — NTHL1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-0.80Z-score

OE missense 1.16 (1.04–1.29)

233 obs / 201.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.03 (0.68–1.59)

0≤0.351.4

Missense OE?1.16 (1.04–1.29)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 14 / 13.6Missense obs/exp: 233 / 201.2Syn Z: 0.41

ClinVar Variant Classifications

1830 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic112

Likely Pathogenic62

VUS967

Likely Benign543

Benign6

Conflicting137

112

Pathogenic

Likely Pathogenic

967

VUS

543

Likely Benign

Benign

137

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	91	0	21	0	112
Likely Pathogenic	59	0	3	0	62
VUS	16	837	108	6	967
Likely Benign	1	15	209	318	543
Benign	0	0	6	0	6
Conflicting	—				137
Total	167	852	347	324	1,827

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

View in ClinVar →

51 pathogenic / likely-pathogenic (of 70) ClinVar copy-number / structural variants overlap NTHL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →