Is TYMS p.Arg115Ter (c.343C>T) pathogenic?

TYMS p.Arg115Ter (c.343C>T) is classified Pathogenic in TYMS (ClinVar, Single submitter, 2 submitters; last evaluated 2022-06-22). Very rare (popmax 0.000678%, nfe); Associated with dyskeratosis congenita.

What condition is associated with TYMS p.Arg115Ter (c.343C>T)?

TYMS p.Arg115Ter (c.343C>T) is associated with dyskeratosis congenita, dyskeratosis congenita, digenic (ClinVar).

How common is TYMS p.Arg115Ter (c.343C>T) in the general population?

TYMS p.Arg115Ter (c.343C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

How is Dyskeratosis congenita inherited?

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

TYMS p.Arg115Ter

c.343C>T · rs2046518776 · VCV1693535

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

dyskeratosis congenita

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 7
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.9, phastCons 1
Overall
CADD	40.0	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 0.000678% European (non-Finnish) · 8/1,179,906 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,613,772 alleles · very rare exomes 9/1,461,636 · genomes 0/152,136 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)grpmax	0.000678%	147,488

Remaining individuals 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: TYMS
Protein: p.Arg115Ter
Coding: c.343C>T
MANE Select: NM_001071
dbSNP: rs2046518776
Type: single nucleotide variant
Location: chr18:662209 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.05 · 61 PDB
Residue 115: a UniProt-annotated variant site (in dkcd; reduced tyms levels in patient cells)

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

Disease context

dyskeratosis congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita, digenic

For Dyskeratosis congenita (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

TYMS p.Glu87Lys Uncertain significance ★ ⚠ same condition
TYMS p.Met179Ter Pathogenic ★ same condition
TYMS p.Ala4Ser Uncertain significance ★ ⚠ same type
TYMS p.Asp148Glu Uncertain significance ★ ⚠ same type
TYMS p.Gly29Arg Uncertain significance ★ ⚠ same type
TYMS p.Pro15Arg Uncertain significance ★ ⚠ same type
TYMS p.Pro15His Uncertain significance ★ ⚠ same type
TYMS p.Pro24Thr 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/tyms-p-arg115ter (accessed [today's date]).

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