Is DSP p.Arg1400Leu (c.4199G>T) pathogenic?

DSP p.Arg1400Leu (c.4199G>T) is classified Uncertain significance in DSP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.1801); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

How common is DSP p.Arg1400Leu (c.4199G>T) in the general population?

DSP p.Arg1400Leu (c.4199G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DSP p.Arg1400Leu (c.4199G>T)?

AlphaMissense predicts likely benign (score 0.1801) — an in-silico prediction, not a clinical call.

DSP p.Arg1400Leu

Q: What condition is associated with DSP p.Arg1400Leu (c.4199G>T)?

DSP p.Arg1400Leu (c.4199G>T) is associated with Cardiovascular phenotype, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, arrhythmogenic right ventricular dysplasia 8 (ClinVar).

c.4199G>T · rs748109826 · VCV2587392

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1801 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,020)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1801	likely benign
REVEL	0.476	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP -0.24, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.0024 · regional, not allelic
Overall
CADD	20.3	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

No allele count reported in gnomAD v4.1 (AN 1,614,020). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: DSP
Protein: p.Arg1400Leu
Coding: c.4199G>T
MANE Select: NM_004415
dbSNP: rs748109826
Type: single nucleotide variant
Location: chr6:7580389 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1400: a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); 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

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

Also linked: arrhythmogenic cardiomyopathy with wooly hair and keratoderma arrhythmogenic right ventricular dysplasia 8

Similar variants

DSP p.Arg1400Ter Pathogenic/Likely pathogenic ★★ same residue
DSP p.Arg1400= Likely benign ★★ same residue
DSP p.Arg1400Gln Conflicting classifications of pathogenicity ★ same residue
DSP p.Arg1400Gly 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-arg1400leu (accessed [today's date]).

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