Is TK2 p.Pro41His (c.122C>A) pathogenic?

TK2 p.Pro41His (c.122C>A) is classified Conflicting classifications of pathogenicity in TK2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0927); Rare (popmax 0.661%, mid); Associated with mitochondrial DNA depletion syndrome, myopathic form.

What condition is associated with TK2 p.Pro41His (c.122C>A)?

TK2 p.Pro41His (c.122C>A) is associated with mitochondrial DNA depletion syndrome, myopathic form (ClinVar).

How common is TK2 p.Pro41His (c.122C>A) in the general population?

TK2 p.Pro41His (c.122C>A) is rare (popmax 0.661%, mid) (gnomAD).

What do computational predictors say about TK2 p.Pro41His (c.122C>A)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

TK2 p.Pro41His

Q: How is Mitochondrial DNA depletion syndrome, myopathic form inherited?

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

c.122C>A · rs201904720 · VCV215262

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.661%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

mitochondrial DNA depletion syndrome, myopathic form

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.371	indeterminate
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.096	GERP -2.9, phastCons 0.082
Regional constraint	o/e 0.91	unconstrained · MANE · 38 kb · p 0.097 · regional, not allelic
Overall
CADD	9.833	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 0.661% Middle Eastern · 24/3,630 alleles

Filtering AF 0.456% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.388%

Overall 0.0714% 967/1,354,004 alleles · rare exomes 838/1,201,714 · genomes 129/152,290 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.08%	93
Middle Easterngrpmax	0.661%	151
Remaining individualsnot grpmax-eligible	0.195%	514
Admixed American	0.118%	845
European (non-Finnish)	0.0526%	1,903
South Asian	0.0492%	2,034
African / African-American	0.0259%	3,862

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro41His
Coding: c.122C>A
MANE Select: NM_004614
dbSNP: rs201904720
Type: single nucleotide variant
Location: chr16:66549940 (GRCh38)

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

Disease context

mitochondrial DNA depletion syndrome, myopathic form — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial DNA depletion syndrome, myopathic form (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

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-pro41his (accessed [today's date]).

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