Is TPP1 p.Pro554Ser (c.1660C>T) pathogenic?

TPP1 p.Pro554Ser (c.1660C>T) is classified Uncertain significance in TPP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-04). AlphaMissense: likely benign (0.1245); Very rare (popmax 0.00401%, afr).

How common is TPP1 p.Pro554Ser (c.1660C>T) in the general population?

TPP1 p.Pro554Ser (c.1660C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about TPP1 p.Pro554Ser (c.1660C>T)?

AlphaMissense predicts likely benign (score 0.1245) — an in-silico prediction, not a clinical call.

TPP1 p.Pro554Ser

c.1660C>T · rs868090227 · VCV960462

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1245 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1245	likely benign
REVEL	0.7	pathogenic-leaning
SaProt	LLR -9.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	24.8	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 0.00401% African / African-American · 3/74,906 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,010 alleles · very rare exomes 1/1,461,888 · genomes 2/152,122 · 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.Pro554Ser
Coding: c.1660C>T
MANE Select: NM_000391
dbSNP: rs868090227
Type: single nucleotide variant
Location: chr11:6614578 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 554: an α-helix; the peptidase s53 domain

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

Similar variants

TPP1 p.Pro554= 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
TPP1 c.1551+1G>C 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-pro554ser (accessed [today's date]).

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