Is DSP p.Val2219Ile (c.6655G>A) pathogenic?

DSP p.Val2219Ile (c.6655G>A) is classified Benign/Likely benign in DSP (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0769); Rare (popmax 0.417%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Val2219Ile (c.6655G>A)?

DSP p.Val2219Ile (c.6655G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Val2219Ile (c.6655G>A) in the general population?

DSP p.Val2219Ile (c.6655G>A) is rare (popmax 0.417%, sas) (gnomAD).

What do computational predictors say about DSP p.Val2219Ile (c.6655G>A)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

DSP p.Val2219Ile

c.6655G>A · rs397516953 · VCV44940

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.417%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.041	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 696 bp · p 9.7e-06 · regional, not allelic
Overall
CADD	14.67	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 0.417% South Asian · 380/91,076 alleles

Filtering AF 0.383% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.369%

Overall 0.0263% 424/1,614,092 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.417%	240
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0288%	3,473
East Asian	0.00668%	14,963
Admixed American	0.00167%	60,022
Finnishnot grpmax-eligible	0.00156%	63,950
European (non-Finnish)	0.00153%	65,557
African / African-American	0.00133%	75,038

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.Val2219Ile
Coding: c.6655G>A
MANE Select: NM_004415
dbSNP: rs397516953
Type: single nucleotide variant
Location: chr6:7583917 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2219: a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); a UniProt-annotated variant site (in dcwhk; uncertain significance; abolishes expression in the myocardium); a UniProt-annotated variant site (in ebla; uncertain significance); an α-helix; the 'binds to telomeres' region; the 'globular 2' region; 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

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

Also linked: cardiomyopathy arrhythmogenic cardiomyopathy with wooly hair and keratoderma arrhythmogenic right ventricular dysplasia 8 lethal acantholytic epidermolysis bullosa keratosis palmoplantaris striata 2 cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis woolly hair-skin fragility syndrome

Similar variants

DSP p.Val2219= Likely benign ★★ 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-val2219ile (accessed [today's date]).

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