Is TPP1 p.Arg447Pro (c.1340G>C) pathogenic?

TPP1 p.Arg447Pro (c.1340G>C) is classified Likely pathogenic in TPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-04). AlphaMissense: likely pathogenic (0.9881); Absent from gnomAD v4.1; Associated with neuronal ceroid lipofuscinosis 2.

What condition is associated with TPP1 p.Arg447Pro (c.1340G>C)?

TPP1 p.Arg447Pro (c.1340G>C) is associated with neuronal ceroid lipofuscinosis 2 (ClinVar).

How common is TPP1 p.Arg447Pro (c.1340G>C) in the general population?

TPP1 p.Arg447Pro (c.1340G>C) is absent from gnomAD v4.1 (gnomAD).

How is CLN2 disease inherited?

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

What do computational predictors say about TPP1 p.Arg447Pro (c.1340G>C)?

AlphaMissense predicts likely pathogenic (score 0.9881) — an in-silico prediction, not a clinical call.

TPP1 p.Arg447Pro

c.1340G>C · rs119455956 · VCV996030

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9881 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 2

Computational evidence

Protein change
AlphaMissense	0.9881	likely pathogenic ✓ concordant with ClinVar · top 2% in TPP1
REVEL	0.969	strongly pathogenic-leaning
SaProt	LLR -15.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TPP1
Protein: p.Arg447Pro
Coding: c.1340G>C
MANE Select: NM_000391
dbSNP: rs119455956
Type: single nucleotide variant
Location: chr11:6615256 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 447: a β-strand; the peptidase s53 domain; a UniProt-annotated variant site (in cln2; displays very low residual enzyme activity; altered intracellular trafficking; demonstrates enhanced processing in response to folding improvement treatment; shows a five fold increase under permissive temperature conditions)

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

For CLN2 disease (Orphanet):

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

Similar variants

TPP1 p.Arg447His Pathogenic/Likely pathogenic ★★ same residue
TPP1 p.Arg447Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TPP1 p.Arg447Leu 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

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-arg447pro (accessed [today's date]).

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