Is DSP p.Asn757Ser (c.2270A>G) pathogenic?

DSP p.Asn757Ser (c.2270A>G) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-27). AlphaMissense: likely benign (0.1188); Ultra-rare (popmax 0.0166%, mid); Associated with cardiomyopathy.

How common is DSP p.Asn757Ser (c.2270A>G) in the general population?

DSP p.Asn757Ser (c.2270A>G) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about DSP p.Asn757Ser (c.2270A>G)?

AlphaMissense predicts likely benign (score 0.1188) — an in-silico prediction, not a clinical call.

DSP p.Asn757Ser

Q: What condition is associated with DSP p.Asn757Ser (c.2270A>G)?

DSP p.Asn757Ser (c.2270A>G) is associated with cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, arrhythmogenic right ventricular dysplasia 8 (ClinVar).

c.2270A>G · rs372354883 · VCV923378

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1188 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1188	likely benign
REVEL	0.336	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.0024 · regional, not allelic
Overall
CADD	23.5	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 0.0166% Middle Eastern · 1/6,024 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000867% 14/1,613,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,024
African / African-American	0.00267%	37,463
East Asian	0.00223%	44,860
Finnishnot grpmax-eligible	0.00156%	64,036
European (non-Finnish)	0.000763%	131,105

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: DSP
Protein: p.Asn757Ser
Coding: c.2270A>G
MANE Select: NM_004415
dbSNP: rs372354883
Type: single nucleotide variant
Location: chr6:7574225 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 757: a UniProt-annotated variant site (in arvd8; uncertain significance); the 'globular 1' region; the 'interaction with mapre1' region; a UniProt-annotated variant site (in dcwhkta; uncertain significance); a UniProt-annotated variant site (in arvd8; likely pathogenic; results in an unstable protein that forms perinuclear aggregates); a UniProt-annotated variant site (in arvd8 and dcwhkta; uncertain significance); a UniProt-annotated variant site (in arvd8)

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

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arrhythmogenic cardiomyopathy with wooly hair and keratoderma arrhythmogenic right ventricular dysplasia 8

Similar variants

DSP c.1141-2A>T Likely pathogenic ★★ same condition
DSP c.1266+2T>C Likely pathogenic ★★ same condition
DSP c.1574+1G>A Likely pathogenic ★★ same condition
DSP c.2130+1G>A Pathogenic/Likely pathogenic ★★ same condition
DSP c.2297+1G>A Likely pathogenic ★★ same condition
DSP c.2298-1G>C Likely pathogenic ★★ same condition
DSP c.2298-2A>C Pathogenic/Likely pathogenic ★★ same condition
DSP c.2437-1G>C Likely pathogenic ★★ same condition

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/dsp-p-asn757ser (accessed [today's date]).

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