Is DSP p.Val495Met (c.1483G>A) pathogenic?

DSP p.Val495Met (c.1483G>A) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.9536); Very rare (popmax 0.00254%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Val495Met (c.1483G>A)?

DSP p.Val495Met (c.1483G>A) is associated with Cardiovascular phenotype, cardiomyopathy, ventricular tachycardia (ClinVar).

How common is DSP p.Val495Met (c.1483G>A) in the general population?

DSP p.Val495Met (c.1483G>A) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about DSP p.Val495Met (c.1483G>A)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

DSP p.Val495Met

c.1483G>A · rs372014020 · VCV228635

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic · top 10% in DSP
REVEL	0.719	pathogenic-leaning
SaProt	LLR -10.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	30.0	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 0.00254% European (non-Finnish) · 30/1,180,030 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.0109% 176/1,614,082 alleles · very rare exomes 160/1,461,892 · genomes 16/152,190 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.409%	245
Remaining individualsnot grpmax-eligible	0.0336%	2,976
European (non-Finnish)grpmax	0.00254%	39,334
East Asian	0.00223%	44,896
South Asian	0.0022%	45,543
Admixed American	0.00167%	60,018

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val495Met
Coding: c.1483G>A
MANE Select: NM_004415
dbSNP: rs372014020
Type: single nucleotide variant
Location: chr6:7569249 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 495: a β-strand; the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; the sh3 domain; a UniProt-annotated variant site (in arvd8; uncertain significance); 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

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

Also linked: cardiomyopathy ventricular tachycardia arrhythmogenic cardiomyopathy with wooly hair and keratoderma arrhythmogenic right ventricular dysplasia 8 lethal acantholytic epidermolysis bullosa woolly hair-skin fragility syndrome

Similar variants

DSP p.Val495Ala Uncertain significance ★★ ⚠ same residue
DSP p.Val495Leu Uncertain significance ★★ same residue
DSP p.Val495= Likely benign ★★ same residue
DSP p.Val495Gly Uncertain significance ★ ⚠ same residue
DSP p.Val495Phe 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

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-val495met (accessed [today's date]).

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