Is TK1 p.Arg41Cys (c.121C>T) pathogenic?

TK1 p.Arg41Cys (c.121C>T) is classified Uncertain significance in TK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: ambiguous (0.3668); Very rare (popmax 0.00839%, amr).

How common is TK1 p.Arg41Cys (c.121C>T) in the general population?

TK1 p.Arg41Cys (c.121C>T) is very rare (popmax 0.00839%, amr) (gnomAD).

What do computational predictors say about TK1 p.Arg41Cys (c.121C>T)?

AlphaMissense predicts ambiguous (score 0.3668) — an in-silico prediction, not a clinical call.

TK1 p.Arg41Cys

c.121C>T · VCV4184897

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00839%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3668	ambiguous
REVEL	0.691	pathogenic-leaning
SaProt	LLR -13.07	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 8.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 12 kb · p 0.00027 · regional, not allelic
Overall
CADD	34.0	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 0.00839% Admixed American · 5/59,576 alleles

Filtering AF 0.00325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.00124% 20/1,611,970 alleles · very rare exomes 20/1,461,578 · genomes 0/150,392 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00839%	11,915
Remaining individualsnot grpmax-eligible	0.0048%	20,814
East Asian	0.00223%	44,834
South Asian	0.0011%	90,946
European (non-Finnish)	0.000848%	117,949

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: TK1
Protein: p.Arg41Cys
Coding: c.121C>T
MANE Select: NM_003258
Type: single nucleotide variant
Location: chr17:78185143 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.72 · 4 PDB
Residue 41: an α-helix

Full TK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TK1 p.Ala198= Benign ★★ same type
TK1 p.Ala151Val Uncertain significance ★ ⚠ same type
TK1 p.Ala193Thr Uncertain significance ★ ⚠ same type
TK1 p.Arg186Trp Uncertain significance ★ ⚠ same type
TK1 p.Arg39Cys Uncertain significance ★ ⚠ same type
TK1 p.Arg60His Uncertain significance ★ ⚠ same type
TK1 p.Arg70Trp Uncertain significance ★ ⚠ same type
TK1 p.Arg82Gln Uncertain significance ★ ⚠ 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/tk1-p-arg41cys (accessed [today's date]).

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