Is DPYS p.Lys159fs (c.476del) pathogenic?

DPYS p.Lys159fs (c.476del) is classified Pathogenic in DPYS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). Ultra-rare (popmax 0.0165%, mid).

How common is DPYS p.Lys159fs (c.476del) in the general population?

DPYS p.Lys159fs (c.476del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

DPYS p.Lys159fs

c.476del · VCV3720857

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000137% 2/1,461,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	8.47e-05%	1,180,018

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: DPYS
Protein: p.Lys159fs
Coding: c.476del
MANE Select: NM_001385
Type: Deletion
Location: chr8:104447451 (GRCh38)
Gene constraint: LOEUF 1.029 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 1 PDB
Residue 159: a modified residue (n6-carboxylysine); a binding site; a β-strand

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

Similar variants

DPYS c.1092+5del Likely pathogenic ★★ same type
DPYS p.Ala34fs Pathogenic/Likely pathogenic ★★ same type
DPYS p.His419fs Likely pathogenic ★ same type
DPYS c.*166_*169del Uncertain significance ★ same type
DPYS p.Arg503fs Conflicting classifications of pathogenicity ★ same type
DPYS p.Glu507fs Conflicting classifications of pathogenicity ★ same type
DPYS c.1443+15del Likely benign ★ same type
DPYS c.423+20del Likely benign ★ 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/dpys-p-lys159fs (accessed [today's date]).

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