Is TPP1 p.Pro145= (c.435T>C) pathogenic?

TPP1 p.Pro145= (c.435T>C) is classified Benign/Likely benign in TPP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-03-04). Very rare (popmax 0.00178%, nfe); Associated with neuronal ceroid lipofuscinosis 2.

What condition is associated with TPP1 p.Pro145= (c.435T>C)?

TPP1 p.Pro145= (c.435T>C) is associated with neuronal ceroid lipofuscinosis 2, autosomal recessive spinocerebellar ataxia 7 (ClinVar).

How common is TPP1 p.Pro145= (c.435T>C) in the general population?

TPP1 p.Pro145= (c.435T>C) is very rare (popmax 0.00178%, nfe) (gnomAD).

How is CLN2 disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TPP1 p.Pro145=

c.435T>C · rs188822344 · VCV378757

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Conditions

neuronal ceroid lipofuscinosis 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.62, phastCons 0.55
Overall
CADD	6.769	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00178% European (non-Finnish) · 21/1,180,024 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0013% 21/1,614,156 alleles · very rare exomes 19/1,461,884 · genomes 2/152,272 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TPP1
Protein: p.Pro145=
Coding: c.435T>C
MANE Select: NM_000391
dbSNP: rs188822344
Type: single nucleotide variant
Location: chr11:6617374 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 145: a turn

Full TPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive spinocerebellar ataxia 7

For CLN2 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

TPP1 p.Pro145Ala Uncertain significance ★ ⚠ same residue
TPP1 c.1075+2T>C Pathogenic/Likely pathogenic ★★ same condition
TPP1 c.1076-2A>G Pathogenic/Likely pathogenic ★★ same condition
TPP1 c.1076-2A>T Pathogenic ★★ same condition
TPP1 c.1146-1G>A Likely pathogenic ★★ same condition
TPP1 c.1425+1G>A Likely pathogenic ★★ same condition
TPP1 c.1551+1G>A Pathogenic/Likely pathogenic ★★ same condition
TPP1 c.1551+1G>C Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tpp1-p-pro145 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown