Is TPP1 p.Phe397Cys (c.1190T>G) pathogenic?

TPP1 p.Phe397Cys (c.1190T>G) is classified Uncertain significance in TPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-28). AlphaMissense: likely pathogenic (0.8203); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TPP1 p.Phe397Cys (c.1190T>G)?

TPP1 p.Phe397Cys (c.1190T>G) is associated with Inborn genetic diseases (ClinVar).

How common is TPP1 p.Phe397Cys (c.1190T>G) in the general population?

TPP1 p.Phe397Cys (c.1190T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPP1 p.Phe397Cys (c.1190T>G)?

AlphaMissense predicts likely pathogenic (score 0.8203) — an in-silico prediction, not a clinical call.

TPP1 p.Phe397Cys

c.1190T>G · rs1431597778 · VCV1744826

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8203 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8203	likely pathogenic
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -4.75	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	28.3	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

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.Phe397Cys
Coding: c.1190T>G
MANE Select: NM_000391
dbSNP: rs1431597778
Type: single nucleotide variant
Location: chr11:6615518 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TPP1 p.Phe397Leu Uncertain significance ★ ⚠ same residue
TPP1 p.Phe397= Likely benign ★ same residue
TPP1 c.17+2T>A Likely pathogenic ★★ same condition
TPP1 c.509-1G>A Pathogenic ★★ same condition
TPP1 p.Ala335Thr Uncertain significance ★★ ⚠ same condition
TPP1 p.Arg208Gln Uncertain significance ★★ ⚠ same condition
TPP1 p.Arg245Cys Uncertain significance ★★ ⚠ same condition
TPP1 p.Arg259Cys Uncertain significance ★★ ⚠ 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-phe397cys (accessed [today's date]).

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