Is DSP p.Glu21Lys (c.61G>A) pathogenic?

DSP p.Glu21Lys (c.61G>A) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.5821); Very rare (popmax 0.00221%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Glu21Lys (c.61G>A)?

DSP p.Glu21Lys (c.61G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Glu21Lys (c.61G>A) in the general population?

DSP p.Glu21Lys (c.61G>A) is very rare (popmax 0.00221%, nfe) (gnomAD).

What do computational predictors say about DSP p.Glu21Lys (c.61G>A)?

AlphaMissense predicts likely pathogenic (score 0.5821) — an in-silico prediction, not a clinical call.

DSP p.Glu21Lys

c.61G>A · rs747956457 · VCV465903

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.5821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5821	likely pathogenic
REVEL	0.275	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	24.4	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 0.00221% European (non-Finnish) · 26/1,177,238 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.002% 29/1,453,528 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0068%	14,704
European (non-Finnish)grpmax	0.00221%	45,278
Remaining individualsnot grpmax-eligible	0.00161%	62,120

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.Glu21Lys
Coding: c.61G>A
MANE Select: NM_004415
dbSNP: rs747956457
Type: single nucleotide variant
Location: chr6:7541976 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 21: the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; a UniProt-annotated variant site (in arvd8; uncertain significance)

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

Similar variants

DSP p.Glu21Asp 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
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-glu21lys (accessed [today's date]).

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