Is TK2 p.Ser61Gly (c.181A>G) pathogenic?

TK2 p.Ser61Gly (c.181A>G) is classified Conflicting classifications of pathogenicity in TK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: ambiguous (0.458); Very rare (popmax 0.000169%, nfe).

How common is TK2 p.Ser61Gly (c.181A>G) in the general population?

TK2 p.Ser61Gly (c.181A>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TK2 p.Ser61Gly (c.181A>G)?

AlphaMissense predicts ambiguous (score 0.458) — an in-silico prediction, not a clinical call.

TK2 p.Ser61Gly

c.181A>G · rs747276038 · VCV421862

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.458 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.458	ambiguous
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -8.04	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	27.0	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 0.000169% European (non-Finnish) · 2/1,180,014 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,106 alleles · very rare exomes 2/1,461,878 · genomes 0/152,228 · 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: TK2
Protein: p.Ser61Gly
Coding: c.181A>G
MANE Select: NM_004614
dbSNP: rs747276038
Type: single nucleotide variant
Location: chr16:66541929 (GRCh38)
Gene constraint: LOEUF 1.101 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 61: a binding site

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

Similar variants

TK2 p.Ser61Asn Uncertain significance ★ ⚠ same residue
TK2 p.Ser61= Likely benign ★ same residue
TK2 c.156+2T>C Pathogenic/Likely pathogenic ★★ same type
TK2 c.157-2A>G Pathogenic/Likely pathogenic ★★ same type
TK2 p.Ala139Thr Pathogenic/Likely pathogenic ★★ same type
TK2 p.Ala139Val Pathogenic/Likely pathogenic ★★ same type
TK2 p.Arg104Cys Pathogenic/Likely pathogenic ★★ same type
TK2 p.Arg130Gln Pathogenic/Likely pathogenic ★★ ⚠ 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-ser61gly (accessed [today's date]).

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