Is DSPP p.Ser1220Arg (c.3660C>A) pathogenic?

DSPP p.Ser1220Arg (c.3660C>A) is classified Uncertain significance in DSPP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-20). AlphaMissense: likely pathogenic (0.6151); Ultra-rare (popmax 0.0363%, afr); Associated with Inborn genetic diseases.

What condition is associated with DSPP p.Ser1220Arg (c.3660C>A)?

DSPP p.Ser1220Arg (c.3660C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DSPP p.Ser1220Arg (c.3660C>A) in the general population?

DSPP p.Ser1220Arg (c.3660C>A) is ultra-rare (popmax 0.0363%, afr) (gnomAD).

What do computational predictors say about DSPP p.Ser1220Arg (c.3660C>A)?

AlphaMissense predicts likely pathogenic (score 0.6151) — an in-silico prediction, not a clinical call.

DSPP p.Ser1220Arg

c.3660C>A · rs778585862 · VCV497435

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6151 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6151	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -11.93	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 -3
Regional constraint	o/e 0.72	unconstrained · MANE · 391 bp · p 0.00018 · regional, not allelic
Overall
CADD	0.51	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 0.0363% African / African-American · 23/63,432 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00227% 34/1,496,542 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0363%	2,758
Admixed American	0.00421%	23,731
Remaining individualsnot grpmax-eligible	0.00345%	28,958
European (non-Finnish)	0.000627%	159,404

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.Ser1220Arg
Coding: c.3660C>A
dbSNP: rs778585862
Type: single nucleotide variant
Location: chr4:87616322 (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-ser1220arg (accessed [today's date]).

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