Is TPP1 p.Ser381Phe (c.1142C>T) pathogenic?

TPP1 p.Ser381Phe (c.1142C>T) is classified Uncertain significance in TPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-18). AlphaMissense: likely pathogenic (0.9788); Very rare (popmax 0.00134%, afr); Associated with neuronal ceroid lipofuscinosis 2.

What condition is associated with TPP1 p.Ser381Phe (c.1142C>T)?

TPP1 p.Ser381Phe (c.1142C>T) is associated with neuronal ceroid lipofuscinosis 2 (ClinVar).

How common is TPP1 p.Ser381Phe (c.1142C>T) in the general population?

TPP1 p.Ser381Phe (c.1142C>T) is very rare (popmax 0.00134%, afr) (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.Ser381Phe (c.1142C>T)?

AlphaMissense predicts likely pathogenic (score 0.9788) — an in-silico prediction, not a clinical call.

TPP1 p.Ser381Phe

c.1142C>T · VCV3775721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9788 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 2

Computational evidence

Protein change
AlphaMissense	0.9788	likely pathogenic · top 4% in TPP1
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -12.86	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	29.9	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 0.00134% African / African-American · 1/74,902 alleles

Overall 6.2e-05% 1/1,614,018 alleles · very rare exomes 0/1,461,832 · genomes 1/152,186 · 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.Ser381Phe
Coding: c.1142C>T
MANE Select: NM_000391
Type: single nucleotide variant
Location: chr11:6616008 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 381: a turn; the peptidase s53 domain

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.Ser381Cys Uncertain significance ★★ ⚠ same residue
TPP1 p.Ser381= 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-ser381phe (accessed [today's date]).

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