Is DSG2 p.Leu29Ser (c.86T>C) pathogenic?

DSG2 p.Leu29Ser (c.86T>C) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-25). AlphaMissense: likely benign (0.1453); Ultra-rare (popmax 0.0147%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Leu29Ser (c.86T>C)?

DSG2 p.Leu29Ser (c.86T>C) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Leu29Ser (c.86T>C) in the general population?

DSG2 p.Leu29Ser (c.86T>C) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about DSG2 p.Leu29Ser (c.86T>C)?

AlphaMissense predicts likely benign (score 0.1453) — an in-silico prediction, not a clinical call.

DSG2 p.Leu29Ser

c.86T>C · rs786205361 · VCV191625

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1453 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1453	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -5.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	16.29	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 0.0147% African / African-American · 11/74,944 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000929% 15/1,614,080 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,813
Admixed American	0.00333%	30,003
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	8.47e-05%	1,180,016

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.Leu29Ser
Coding: c.86T>C
MANE Select: NM_001943
dbSNP: rs786205361
Type: single nucleotide variant
Location: chr18:31519807 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB

Full DSG2 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 right ventricular dysplasia 10

Similar variants

DSG2 p.Leu29Phe Uncertain significance ★ ⚠ same residue
DSG2 p.Leu29fs Pathogenic/Likely pathogenic ★★ 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-leu29ser (accessed [today's date]).

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