Is DSPP p.Asp1227Glu (c.3681C>A) pathogenic?

DSPP p.Asp1227Glu (c.3681C>A) is classified Benign/Likely benign in DSPP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-02-16). AlphaMissense: likely benign (0.249); Common (popmax 12.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with deafness, autosomal dominant 39, with dentinogenesis imperfecta 1.

What condition is associated with DSPP p.Asp1227Glu (c.3681C>A)?

DSPP p.Asp1227Glu (c.3681C>A) is associated with deafness, autosomal dominant 39, with dentinogenesis imperfecta 1 (ClinVar).

What do computational predictors say about DSPP p.Asp1227Glu (c.3681C>A)?

AlphaMissense predicts likely benign (score 0.249) — an in-silico prediction, not a clinical call.

DSPP p.Asp1227Glu

Q: How common is DSPP p.Asp1227Glu (c.3681C>A) in the general population?

DSPP p.Asp1227Glu (c.3681C>A) is common (popmax 12.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3681C>A · rs959216315 · VCV523082

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.249 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

deafness, autosomal dominant 39, with dentinogenesis imperfecta 1

Computational evidence

Protein change
AlphaMissense	0.249	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -20	GERP -3.2
Regional constraint	o/e 0.72	unconstrained · MANE · 391 bp · p 0.00018 · regional, not allelic
Overall
CADD	0.042	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.4% African / African-American · 5,728/46,124 alleles

Filtering AF 12.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 12%

Overall 1.45% 20,105/1,384,104 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.4%	8
Finnishnot grpmax-eligible	4.43%	23
Ashkenazi Jewishnot grpmax-eligible	2.54%	39
Middle Eastern	2.44%	41
Remaining individualsnot grpmax-eligible	2.05%	49
Admixed American	1.52%	66
South Asian	1.16%	87
European (non-Finnish)	0.815%	123
East Asian	0.383%	261

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.Asp1227Glu
Coding: c.3681C>A
dbSNP: rs959216315
Type: single nucleotide variant
Location: chr4:87616343 (GRCh38)

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

Disease context

deafness, autosomal dominant 39, with dentinogenesis imperfecta 1 — 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-asp1227glu (accessed [today's date]).

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