Is DSP p.Ser22Cys (c.65C>G) pathogenic?

DSP p.Ser22Cys (c.65C>G) is classified Uncertain significance in DSP (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-18). AlphaMissense: likely benign (0.2041); Very rare (popmax 0.00224%, sas); Associated with arrhythmogenic right ventricular dysplasia 8.

What condition is associated with DSP p.Ser22Cys (c.65C>G)?

DSP p.Ser22Cys (c.65C>G) is associated with arrhythmogenic right ventricular dysplasia 8, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

How common is DSP p.Ser22Cys (c.65C>G) in the general population?

DSP p.Ser22Cys (c.65C>G) is very rare (popmax 0.00224%, sas) (gnomAD).

What do computational predictors say about DSP p.Ser22Cys (c.65C>G)?

AlphaMissense predicts likely benign (score 0.2041) — an in-silico prediction, not a clinical call.

DSP p.Ser22Cys

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.65C>G · rs2533800831 · VCV2130501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2041 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

arrhythmogenic right ventricular dysplasia 8

Computational evidence

Protein change
AlphaMissense	0.2041	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	27.1	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 0.00224% South Asian · 2/89,310 alleles

Filtering AF 0.000372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000139%

Overall 0.000125% 2/1,604,492 alleles · very rare exomes 2/1,452,162 · genomes 0/152,330 · joint denominator

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.Ser22Cys
Coding: c.65C>G
MANE Select: NM_004415
dbSNP: rs2533800831
Type: single nucleotide variant
Location: chr6:7541980 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 22: the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; a modified residue (phosphoserine)

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

Disease context

arrhythmogenic right ventricular dysplasia 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSP p.Ser22Pro Uncertain significance ★ same residue
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

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-ser22cys (accessed [today's date]).

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