Is DSP p.Asp1251fs (c.3751del) pathogenic?

DSP p.Asp1251fs (c.3751del) is classified Likely pathogenic in DSP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-01). Very rare (popmax 0.000657%).

How common is DSP p.Asp1251fs (c.3751del) in the general population?

DSP p.Asp1251fs (c.3751del) is very rare (popmax 0.000657%) (gnomAD).

DSP p.Asp1251fs

c.3751del · rs1464644246 · VCV2578993

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000657%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 23 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Overall
CADD	27.6	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 0.000657%

Overall 0.000657% 1/152,246 alleles · very rare

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: DSP
Protein: p.Asp1251fs
Coding: c.3751del
MANE Select: NM_004415
dbSNP: rs1464644246
Type: Deletion
Location: chr6:7579940 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1251: a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); the 'central fibrous rod domain' region; the 'binds to telomeres' region; a UniProt-annotated variant site (in arvd8; likely pathogenic; results in an unstable protein that forms perinuclear aggregates); a UniProt-annotated variant site (in arvd8 and dcwhkta; uncertain significance); a UniProt-annotated variant site (in arvd8)

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

Similar variants

DSP p.Asp1251= Likely benign ★★ same residue
DSP c.2131-3_2131del Likely pathogenic ★★ same type
DSP p.Ala2092fs Pathogenic/Likely pathogenic ★★ same type
DSP p.Arg1113fs Pathogenic ★★ same type
DSP p.Arg1173fs Pathogenic ★★ same type
DSP p.Arg1506fs Pathogenic/Likely pathogenic ★★ same type
DSP p.Asn1346fs Pathogenic/Likely pathogenic ★★ same type
DSP p.Asn257fs 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/dsp-p-asp1251fs (accessed [today's date]).

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