Is DSPP p.Ser1226= (c.3678C>T) pathogenic?

DSPP p.Ser1226= (c.3678C>T) is classified Benign/Likely benign in DSPP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-16). Common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele.

DSPP p.Ser1226=

Q: How common is DSPP p.Ser1226= (c.3678C>T) in the general population?

DSPP p.Ser1226= (c.3678C>T) is common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3678C>T · rs746564839 · VCV1263085

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 12.8%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -20	GERP -3.4
Overall
CADD	0.084	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.8% African / African-American · 5,764/45,196 alleles

Filtering AF 12.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.4%

Overall 1.49% 20,497/1,377,670 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.8%	8
Finnishnot grpmax-eligible	4.62%	22
Ashkenazi Jewishnot grpmax-eligible	2.58%	39
Middle Eastern	2.49%	40
Remaining individualsnot grpmax-eligible	2.11%	47
Admixed American	1.58%	63
South Asian	1.23%	81
European (non-Finnish)	0.835%	120
East Asian	0.384%	260
Amishnot grpmax-eligible	0.119%	838

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.Ser1226=
Coding: c.3678C>T
dbSNP: rs746564839
Type: single nucleotide variant
Location: chr4:87616340 (GRCh38)

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

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-ser1226 (accessed [today's date]).

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