TPCN2

Chr 11

two pore segment channel 2

Also known as: SHEP10, TPC2

NCBI Gene: 219931ENSG00000162341UniProt: Q8NHX9

This gene encodes a putative cation-selective ion channel with two repeats of a six-transmembrane-domain. The protein localizes to lysosomal membranes and enables nicotinic acid adenine dinucleotide phosphate (NAADP) -induced calcium ion release from lysosome-related stores. This ubiquitously expressed gene has elevated expression in liver and kidney. Two common nonsynonymous SNPs in this gene strongly associate with blond versus brown hair pigmentation.[provided by RefSeq, Dec 2009]

Primary Disease Associations & Inheritance

[Skin/hair/eye pigmentation 10, blond/brown hair]MIM #612267
158
ClinVar variants
10
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TPCN2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
10 Pathogenic / Likely Pathogenic· 129 VUS of 158 total submissions

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.
0.69LOEUF
pLI 0.000
Z-score 3.30
OE 0.49 (0.35–0.69)
Tolerant

Typical tolerance to LoF variation

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.
0.45Z-score
OE missense 0.94 (0.87–1.02)
412 obs / 438.6 exp
Tolerant

Mild missense constraint

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.0.49 (0.35–0.69)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.87–1.02)
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.0.97
0≤1.21.6
LoF obs/exp: 24 / 48.9Missense obs/exp: 412 / 438.6Syn Z: 0.35

ClinVar Variant Classifications

158 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic5
VUS129
Likely Benign11
Benign8
5
Pathogenic
5
Likely Pathogenic
129
VUS
11
Likely Benign
8
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
5
0
5
Likely Pathogenic
0
1
4
0
5
VUS
0
127
2
0
129
Likely Benign
0
5
4
2
11
Benign
0
4
0
4
8
Total0137156158

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

View in ClinVar →

Protein Context — Lollipop Plot

TPCN2 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

[Skin/hair/eye pigmentation 10, blond/brown hair]

MIM #612267

Molecular basis of disorder known

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A patient with TPCN2-related hypopigmentation and ocular phenotype.
Courdier C et al.·Eur J Hum Genet
2025Case report
Genetics of pigmentation and melanoma predisposition.
Pho LN et al.·G Ital Dermatol Venereol
2010Review
Genetic Variants of TPCN2 Associated with Type 2 Diabetes Risk in the Chinese Population.
Fan Y et al.·PLoS One
2016
Molecular genetics of human pigmentation diversity.
Sturm RA·Hum Mol Genet
2009Review
Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population.
Wen L et al.·Ann Rheum Dis
2018
Distinct genetic risk loci between biopsy-proven renal and non-renal lupus: a 10-year longitudinal cohort.
Chan SCW et al.·Rheumatology (Oxford)
2025Cohort
Missing Heritability in Albinism: Deep Characterization of a Hungarian Albinism Cohort Raises the Possibility of the Digenic Genetic Background of the Disease.
Nagy N et al.·Int J Mol Sci
2024Cohort
Identification of a novel gene for diabetic traits in rats, mice, and humans.
Tsaih SW et al.·Genetics
2014
Integrated Analysis of Coexpression and Exome Sequencing to Prioritize Susceptibility Genes for Familial Cutaneous Melanoma.
Yepes S et al.·J Invest Dermatol
2022
Selected gene polymorphisms effect on skin and hair pigmentation in Polish children at the prepubertal age.
Sitek A et al.·Anthropol Anz
2016
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools