Is DSP p.Ala1622Val (c.4865C>T) pathogenic?

DSP p.Ala1622Val (c.4865C>T) is classified Uncertain significance in DSP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0925); Very rare (popmax 0.00223%, eas); Associated with cardiomyopathy.

What condition is associated with DSP p.Ala1622Val (c.4865C>T)?

DSP p.Ala1622Val (c.4865C>T) is associated with cardiomyopathy (ClinVar).

How common is DSP p.Ala1622Val (c.4865C>T) in the general population?

DSP p.Ala1622Val (c.4865C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DSP p.Ala1622Val (c.4865C>T)?

AlphaMissense predicts likely benign (score 0.0925) — an in-silico prediction, not a clinical call.

DSP p.Ala1622Val

c.4865C>T · rs1759421103 · VCV2453248

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.0925	likely benign
REVEL	0.087	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 0.75	GERP -0.29, phastCons 0.2
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.0024 · regional, not allelic
Overall
CADD	9.888	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,874 alleles

Overall 6.84e-05% 1/1,461,748 alleles · very rare

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.Ala1622Val
Coding: c.4865C>T
MANE Select: NM_004415
dbSNP: rs1759421103
Type: single nucleotide variant
Location: chr6:7581055 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1622: 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); the 'central fibrous rod domain' region; the 'binds to telomeres' 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

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

Similar variants

DSP p.Ala1622Ser Uncertain significance ★ ⚠ same residue
DSP p.Ala1622= Likely benign ★ same residue
DSP c.2130+1G>A Pathogenic/Likely pathogenic ★★ same condition
DSP c.2437-1G>C Likely pathogenic ★★ same condition
DSP c.273+1G>A Pathogenic/Likely pathogenic ★★ same condition
DSP c.939+1G>A Pathogenic/Likely pathogenic ★★ same condition
DSP p.Arg1113Ter Pathogenic/Likely pathogenic ★★ same condition
DSP p.Arg1267Ter 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-ala1622val (accessed [today's date]).

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