Is TK2 p.Ser150fs (c.447_448dup) pathogenic?

TK2 p.Ser150fs (c.447448dup) is classified Pathogenic in TK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-27). Very rare (popmax 0.00195%, nfe).

How common is TK2 p.Ser150fs (c.447_448dup) in the general population?

TK2 p.Ser150fs (c.447_448dup) is very rare (popmax 0.00195%, nfe) (gnomAD).

TK2 p.Ser150fs

c.447_448dup · rs746907276 · VCV1414250

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,886 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,613,770 alleles · very rare exomes 24/1,461,606 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,299
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00134%	74,886

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: TK2
Protein: p.Ser150fs
Coding: c.447_448dup
MANE Select: NM_004614
dbSNP: rs746907276
Type: Duplication
Location: chr16:66528994 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01

Full TK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TK2 p.Ser51fs Pathogenic ★★ same type
TK2 p.Glu48fs Pathogenic ★ same type
TK2 p.Leu131fs Pathogenic ★ same type
TK2 p.Pro227fs Likely pathogenic ★ same type
TK2 p.Trp4fs Pathogenic ★ same type
TK2 p.Val113fs Pathogenic ★ same type
TK2 c.*1756_*1757dup Uncertain significance ★ same type
TK2 c.156+15dup Benign ★ 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/tk2-p-ser150fs (accessed [today's date]).

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