Is DSG2 p.His74Arg (c.221A>G) pathogenic?

DSG2 p.His74Arg (c.221A>G) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1323); Rare (popmax 0.326%, afr); Associated with cardiomyopathy.

What condition is associated with DSG2 p.His74Arg (c.221A>G)?

DSG2 p.His74Arg (c.221A>G) is associated with cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.His74Arg (c.221A>G) in the general population?

DSG2 p.His74Arg (c.221A>G) is rare (popmax 0.326%, afr) (gnomAD).

What do computational predictors say about DSG2 p.His74Arg (c.221A>G)?

AlphaMissense predicts likely benign (score 0.1323) — an in-silico prediction, not a clinical call.

DSG2 p.His74Arg

c.221A>G · rs201855245 · VCV227340

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1323 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.326%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1323	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -3.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	19.98	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 0.326% African / African-American · 245/75,040 alleles

Filtering AF 0.293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.28%

Overall 0.0172% 277/1,613,584 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.326%	306
Admixed American	0.0317%	3,157
Remaining individualsnot grpmax-eligible	0.0176%	5,680
European (non-Finnish)	0.00017%	589,856

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: DSG2
Protein: p.His74Arg
Coding: c.221A>G
MANE Select: NM_001943
dbSNP: rs201855245
Type: single nucleotide variant
Location: chr18:31520807 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 74: the cadherin 1 domain

Full DSG2 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

Also linked: arrhythmogenic right ventricular dysplasia 10

Similar variants

DSG2 p.His74Asn Uncertain significance ★★ ⚠ same residue
DSG2 p.His74= Likely benign ★★ same residue
DSG2 c.1423+1G>T Likely pathogenic ★★ same condition
DSG2 c.1424-1G>A Likely pathogenic ★★ same condition
DSG2 c.523+1G>T Pathogenic/Likely pathogenic ★★ same condition
DSG2 c.690+1G>A Pathogenic ★★ same condition
DSG2 c.81+1G>T Likely pathogenic ★★ same condition
DSG2 c.829-2A>T 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/dsg2-p-his74arg (accessed [today's date]).

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