Is TPK1 p.Pro7Ser (c.19C>T) pathogenic?

TPK1 p.Pro7Ser (c.19C>T) is classified Likely pathogenic in TPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-01). AlphaMissense: likely pathogenic (0.7027); Very rare (popmax 0.00448%, eas); Associated with childhood encephalopathy due to thiamine pyrophosphokinase deficiency.

What condition is associated with TPK1 p.Pro7Ser (c.19C>T)?

TPK1 p.Pro7Ser (c.19C>T) is associated with childhood encephalopathy due to thiamine pyrophosphokinase deficiency (ClinVar).

How common is TPK1 p.Pro7Ser (c.19C>T) in the general population?

TPK1 p.Pro7Ser (c.19C>T) is very rare (popmax 0.00448%, eas) (gnomAD).

What do computational predictors say about TPK1 p.Pro7Ser (c.19C>T)?

AlphaMissense predicts likely pathogenic (score 0.7027) — an in-silico prediction, not a clinical call.

TPK1 p.Pro7Ser

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.19C>T · rs751034120 · VCV972916

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00448%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

childhood encephalopathy due to thiamine pyrophosphokinase deficiency

Computational evidence

Protein change
AlphaMissense	0.7027	likely pathogenic ✓ concordant with ClinVar
REVEL	0.516	indeterminate
SaProt	LLR -12.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 382 kb · p 0.81 · regional, not allelic
Overall
CADD	28.2	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 0.00448% East Asian · 2/44,610 alleles

Filtering AF 0.000743% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000125% 2/1,600,924 alleles · very rare exomes 2/1,448,770 · genomes 0/152,154 · 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: TPK1
Protein: p.Pro7Ser
Coding: c.19C>T
MANE Select: NM_022445
dbSNP: rs751034120
Type: single nucleotide variant
Location: chr7:144835584 (GRCh38)
Gene constraint: LOEUF 1.337 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 97.92 · 2 PDB

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 p.Pro7Leu Uncertain significance ★★ same residue
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

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-pro7ser (accessed [today's date]).

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