Is DSPP p.Ser1046Arg (c.3138C>A) pathogenic?

DSPP p.Ser1046Arg (c.3138C>A) is classified Uncertain significance in DSPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely pathogenic (0.7126); Very rare (popmax 0.00332%, afr); Associated with Inborn genetic diseases.

What condition is associated with DSPP p.Ser1046Arg (c.3138C>A)?

DSPP p.Ser1046Arg (c.3138C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DSPP p.Ser1046Arg (c.3138C>A) in the general population?

DSPP p.Ser1046Arg (c.3138C>A) is very rare (popmax 0.00332%, afr) (gnomAD).

What do computational predictors say about DSPP p.Ser1046Arg (c.3138C>A)?

AlphaMissense predicts likely pathogenic (score 0.7126) — an in-silico prediction, not a clinical call.

DSPP p.Ser1046Arg

c.3138C>A · VCV4015145

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00332%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7126	likely pathogenic
REVEL	0.299	indeterminate
SaProt	LLR -11.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -20	GERP -1.8
Regional constraint	o/e 0.38	unconstrained · MANE · 513 bp · p 9.7e-18 · regional, not allelic
Overall
CADD	0.021	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00332% African / African-American · 2/60,292 alleles

Filtering AF 0.00055% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000206%

Overall 0.000328% 4/1,218,532 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00332%	30,146
Remaining individualsnot grpmax-eligible	0.0019%	52,700
European (non-Finnish)	0.000102%	984,552

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.Ser1046Arg
Coding: c.3138C>A
Type: single nucleotide variant
Location: chr4:87615800 (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-ser1046arg (accessed [today's date]).

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