Is DSG2 p.Pro970Ser (c.2908C>T) pathogenic?

DSG2 p.Pro970Ser (c.2908C>T) is classified Uncertain significance in DSG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-06). AlphaMissense: likely benign (0.1232); Very rare (popmax 0.00224%, eas); Associated with cardiomyopathy.

How common is DSG2 p.Pro970Ser (c.2908C>T) in the general population?

DSG2 p.Pro970Ser (c.2908C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about DSG2 p.Pro970Ser (c.2908C>T)?

AlphaMissense predicts likely benign (score 0.1232) — an in-silico prediction, not a clinical call.

DSG2 p.Pro970Ser

Q: What condition is associated with DSG2 p.Pro970Ser (c.2908C>T)?

DSG2 p.Pro970Ser (c.2908C>T) is associated with cardiomyopathy, arrhythmogenic right ventricular dysplasia 10, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

c.2908C>T · rs758058872 · VCV924924

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1232 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1232	likely benign
REVEL	0.546	indeterminate
SaProt	LLR -8.46	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	22.1	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 0.00224% East Asian · 1/44,726 alleles

Overall 0.000138% 2/1,450,040 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,726
European (non-Finnish)	8.52e-05%	1,173,124

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.Pro970Ser
Coding: c.2908C>T
MANE Select: NM_001943
dbSNP: rs758058872
Type: single nucleotide variant
Location: chr18:31546294 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 970: a UniProt-annotated variant site (in arvd10; uncertain significance; evidence of residual myocardium, fibrous tissue, fatty tissue, dysmetric and dysmorphic nuclei and prominent cytoplasmic vacuolization; decreases the number of desmosomes at intercalated disks also increases desmosome gap; smaller intercellular gaps, with repeating couplings, abnormally located desmosomes and pale internal plaques); a UniProt-annotated variant site (in arvd10; uncertain significance)

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 arrhythmogenic right ventricular cardiomyopathy

Similar variants

DSG2 p.Pro970Ala Uncertain significance ★ ⚠ 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
DSG2 p.Arg46Gln 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/dsg2-p-pro970ser (accessed [today's date]).

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