Is TPK1 p.Ala45= (c.135C>T) pathogenic?

TPK1 p.Ala45= (c.135C>T) is classified Likely benign in TPK1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-02). Ultra-rare (popmax 0.0121%, nfe); Associated with childhood encephalopathy due to thiamine pyrophosphokinase deficiency.

What condition is associated with TPK1 p.Ala45= (c.135C>T)?

TPK1 p.Ala45= (c.135C>T) is associated with childhood encephalopathy due to thiamine pyrophosphokinase deficiency (ClinVar).

How common is TPK1 p.Ala45= (c.135C>T) in the general population?

TPK1 p.Ala45= (c.135C>T) is ultra-rare (popmax 0.0121%, nfe) (gnomAD).

TPK1 p.Ala45=

Q: How is Childhood encephalopathy due to thiamine pyrophosphokinase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.135C>T · rs767900232 · VCV516761

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, nfe)

Conditions

childhood encephalopathy due to thiamine pyrophosphokinase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -3.5
Overall
CADD	9.002	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% European (non-Finnish) · 143/1,179,900 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00981%

Overall 0.00942% 152/1,613,110 alleles · ultra-rare exomes 146/1,461,044 · genomes 6/152,066 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0121%	8,251
Remaining individualsnot grpmax-eligible	0.0096%	10,413
African / African-American	0.00267%	37,442
South Asian	0.0011%	91,076

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: TPK1
Protein: p.Ala45=
Coding: c.135C>T
MANE Select: NM_022445
dbSNP: rs767900232
Type: single nucleotide variant
Location: chr7:144682959 (GRCh38)
Gene constraint: LOEUF 1.337 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.92 · 2 PDB
Residue 45: a β-strand

Full TPK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

childhood encephalopathy due to thiamine pyrophosphokinase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TPK1 c.115+1G>T Likely pathogenic ★★ same condition
TPK1 c.185+1G>A Pathogenic/Likely pathogenic ★★ same condition
TPK1 c.44-2A>G Pathogenic/Likely pathogenic ★★ same condition
TPK1 c.501+4A>T Pathogenic ★★ same condition
TPK1 p.Asp222His Pathogenic/Likely pathogenic ★★ same condition
TPK1 p.Leu142Phe Pathogenic ★★ same condition
TPK1 p.Tyr82Ter Pathogenic/Likely pathogenic ★★ same condition
TPK1 p.Ala43Thr 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/tpk1-p-ala45 (accessed [today's date]).

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