Is DSP p.Arg232His (c.695G>A) pathogenic?

DSP p.Arg232His (c.695G>A) is classified Uncertain significance in DSP (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-01). AlphaMissense: ambiguous (0.3758); Very rare (popmax 0.00668%, eas); Associated with arrhythmogenic right ventricular dysplasia 8.

What condition is associated with DSP p.Arg232His (c.695G>A)?

DSP p.Arg232His (c.695G>A) is associated with arrhythmogenic right ventricular dysplasia 8, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Arg232His (c.695G>A) in the general population?

DSP p.Arg232His (c.695G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about DSP p.Arg232His (c.695G>A)?

AlphaMissense predicts ambiguous (score 0.3758) — an in-silico prediction, not a clinical call.

DSP p.Arg232His

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.695G>A · rs749438581 · VCV1328053

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3758 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Conditions

arrhythmogenic right ventricular dysplasia 8

Computational evidence

Protein change
AlphaMissense	0.3758	ambiguous
REVEL	0.547	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	31.0	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 0.00668% East Asian · 3/44,896 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000558% 9/1,613,972 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,965
African / African-American	0.00133%	74,922
European (non-Finnish)	0.000424%	235,998

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.Arg232His
Coding: c.695G>A
MANE Select: NM_004415
dbSNP: rs749438581
Type: single nucleotide variant
Location: chr6:7562749 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 232: an α-helix; the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; the 'interaction with pkp1' region; a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance)

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: cardiomyopathy arrhythmogenic cardiomyopathy with wooly hair and keratoderma

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSP p.Arg232Cys Conflicting classifications of pathogenicity ★ same residue
DSP p.Arg232= Likely benign ★ same residue
DSP p.Arg232Leu Uncertain significance ★ ⚠ same residue
DSP p.Arg232Ser 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

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-arg232his (accessed [today's date]).

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