Is DSPP p.Ser640fs (c.1918_1921del) pathogenic?

DSPP p.Ser640fs (c.19181921del) is classified Pathogenic/Likely pathogenic in DSPP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-03). Very rare (popmax 8.72e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DSPP p.Ser640fs (c.1918_1921del)?

DSPP p.Ser640fs (c.1918_1921del) is associated with Inborn genetic diseases (ClinVar).

How common is DSPP p.Ser640fs (c.1918_1921del) in the general population?

DSPP p.Ser640fs (c.1918_1921del) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

DSPP p.Ser640fs

c.1918_1921del · VCV3273917

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Conditions

Inborn genetic diseases

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 0.14	GERP 0.46, phastCons 0.041
Overall
CADD	17.61	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CAGTGA)n simple repeat · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.72e-05% European (non-Finnish) · 1/1,146,944 alleles

Overall 0.000657% 1/152,152 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: DSPP
Protein: p.Ser640fs
Coding: c.1918_1921del
Type: Deletion
Location: chr4:87614578 (GRCh38)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/dspp-p-ser640fs (accessed [today's date]).

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