Is TPP1 p.Ser153Pro (c.457T>C) pathogenic?

TPP1 p.Ser153Pro (c.457T>C) is classified Uncertain significance in TPP1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-02-09). AlphaMissense: likely pathogenic (0.8955); Very rare (popmax 0.000169%, nfe); Associated with neuronal ceroid lipofuscinosis 2.

What condition is associated with TPP1 p.Ser153Pro (c.457T>C)?

TPP1 p.Ser153Pro (c.457T>C) is associated with neuronal ceroid lipofuscinosis 2 (ClinVar).

How common is TPP1 p.Ser153Pro (c.457T>C) in the general population?

TPP1 p.Ser153Pro (c.457T>C) is very rare (popmax 0.000169%, nfe) (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.Ser153Pro (c.457T>C)?

AlphaMissense predicts likely pathogenic (score 0.8955) — an in-silico prediction, not a clinical call.

TPP1 p.Ser153Pro

c.457T>C · rs1554902028 · VCV554257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 2

Computational evidence

Protein change
AlphaMissense	0.8955	likely pathogenic
REVEL	0.719	pathogenic-leaning
SaProt	LLR -12.28	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.34	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,990 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,882 alleles · very rare

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.Ser153Pro
Coding: c.457T>C
MANE Select: NM_000391
dbSNP: rs1554902028
Type: single nucleotide variant
Location: chr11:6617352 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 153: a UniProt-annotated variant site (in cln2)

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.Ser153fs Pathogenic ★ same residue
TPP1 p.Ser153= Likely benign ★ 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

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-ser153pro (accessed [today's date]).

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