Is TPP1 p.Pro499= (c.1497T>C) pathogenic?

TPP1 p.Pro499= (c.1497T>C) is classified Benign/Likely benign in TPP1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-28). Rare (popmax 0.515%, afr); Associated with Inborn genetic diseases.

What condition is associated with TPP1 p.Pro499= (c.1497T>C)?

TPP1 p.Pro499= (c.1497T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TPP1 p.Pro499= (c.1497T>C) in the general population?

TPP1 p.Pro499= (c.1497T>C) is rare (popmax 0.515%, afr) (gnomAD).

TPP1 p.Pro499=

c.1497T>C · rs142672910 · VCV137706

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.515%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.2	GERP 1.1, phastCons 1
Overall
CADD	11.39	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.515% African / African-American · 386/75,008 alleles

Filtering AF 0.472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.456%

Overall 0.0279% 450/1,614,116 alleles · rare exomes 212/1,461,878 · genomes 238/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.515%	194
Remaining individualsnot grpmax-eligible	0.0576%	1,736
Admixed American	0.0367%	2,728
Middle Eastern	0.0165%	6,062
South Asian	0.0022%	45,543
European (non-Finnish)	0.000254%	393,342

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.Pro499=
Coding: c.1497T>C
MANE Select: NM_000391
dbSNP: rs142672910
Type: single nucleotide variant
Location: chr11:6614920 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 499: an α-helix; 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.Pro499Ala Uncertain significance ★★ ⚠ same residue
TPP1 p.Pro499Thr Uncertain significance ★★ ⚠ same residue
TPP1 p.Pro499Arg Uncertain significance ★ ⚠ same residue
TPP1 p.Pro499Leu Uncertain significance ★ ⚠ 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

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-pro499 (accessed [today's date]).

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