Is TPP1 p.Phe51Ser (c.152T>C) pathogenic?

TPP1 p.Phe51Ser (c.152T>C) is classified Uncertain significance in TPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). AlphaMissense: likely pathogenic (0.9939); Absent from gnomAD v4.1.

How common is TPP1 p.Phe51Ser (c.152T>C) in the general population?

TPP1 p.Phe51Ser (c.152T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPP1 p.Phe51Ser (c.152T>C)?

AlphaMissense predicts likely pathogenic (score 0.9939) — an in-silico prediction, not a clinical call.

TPP1 p.Phe51Ser

c.152T>C · rs931480136 · VCV2162668

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9939 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9939	likely pathogenic · top 1% in TPP1
REVEL	0.7	pathogenic-leaning
SaProt	LLR -14.54	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	28.0	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

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.Phe51Ser
Coding: c.152T>C
MANE Select: NM_000391
dbSNP: rs931480136
Type: single nucleotide variant
Location: chr11:6618853 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 51: a β-strand

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

Similar variants

TPP1 c.1075+2T>C Pathogenic/Likely pathogenic ★★ same type
TPP1 c.1076-2A>G Pathogenic/Likely pathogenic ★★ same type
TPP1 c.1076-2A>T Pathogenic ★★ same type
TPP1 c.1146-1G>A Likely pathogenic ★★ same type
TPP1 c.1425+1G>A Likely pathogenic ★★ same type
TPP1 c.1551+1G>A Pathogenic/Likely pathogenic ★★ same type
TPP1 c.1551+1G>C Pathogenic/Likely pathogenic ★★ same type
TPP1 c.1551+1G>T Pathogenic/Likely pathogenic ★★ same type

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-phe51ser (accessed [today's date]).

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