Is TYMP p.Leu447fs (c.1340_1361del) pathogenic?

TYMP p.Leu447fs (c.13401361del) is classified Conflicting classifications of pathogenicity in TYMP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-04-26). Very rare (popmax 0.00134%, afr); Associated with mitochondrial DNA depletion syndrome 1.

What condition is associated with TYMP p.Leu447fs (c.1340_1361del)?

TYMP p.Leu447fs (c.1340_1361del) is associated with mitochondrial DNA depletion syndrome 1 (ClinVar).

How common is TYMP p.Leu447fs (c.1340_1361del) in the general population?

TYMP p.Leu447fs (c.1340_1361del) is very rare (popmax 0.00134%, afr) (gnomAD).

TYMP p.Leu447fs

Q: How is Mitochondrial neurogastrointestinal encephalomyopathy inherited?

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

c.1340_1361del · rs772501604 · VCV666945

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

mitochondrial DNA depletion syndrome 1

⚠ 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
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.51	GERP -2.3, phastCons 0.26
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 0.00134% African / African-American · 1/74,420 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000936% 15/1,602,540 alleles · very rare exomes 13/1,450,352 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0163%	6,152
African / African-Americangrpmax	0.00134%	74,420
South Asian	0.00111%	90,372
European (non-Finnish)	0.000255%	391,760

Finnish 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: TYMP
Protein: p.Leu447fs
Coding: c.1340_1361del
MANE Select: NM_001953
dbSNP: rs772501604
Type: Deletion
Location: chr22:50525858 (GRCh38)

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

Disease context

mitochondrial DNA depletion syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Mitochondrial neurogastrointestinal encephalomyopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

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/tymp-p-leu447fs (accessed [today's date]).

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