Is TPP1 p.Phe397Leu (c.1189T>C) pathogenic?

TPP1 p.Phe397Leu (c.1189T>C) is classified Uncertain significance in TPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-30). AlphaMissense: likely pathogenic (0.8888); Very rare (popmax 0.000169%, nfe).

How common is TPP1 p.Phe397Leu (c.1189T>C) in the general population?

TPP1 p.Phe397Leu (c.1189T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TPP1 p.Phe397Leu (c.1189T>C)?

AlphaMissense predicts likely pathogenic (score 0.8888) — an in-silico prediction, not a clinical call.

TPP1 p.Phe397Leu

c.1189T>C · VCV4910489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8888	likely pathogenic
REVEL	0.665	pathogenic-leaning
SaProt	LLR -0.77	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	23.3	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

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,032 alleles

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

Overall 0.000124% 2/1,614,162 alleles · very rare exomes 2/1,461,882 · genomes 0/152,280 · 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.Phe397Leu
Coding: c.1189T>C
MANE Select: NM_000391
Type: single nucleotide variant
Location: chr11:6615519 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 397: a β-strand; the peptidase s53 domain

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

Similar variants

TPP1 p.Phe397Cys Uncertain significance ★ ⚠ same residue
TPP1 p.Phe397= Likely benign ★ same residue
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

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-phe397leu (accessed [today's date]).

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