Is DSG2 p.Val987Phe (c.2959G>T) pathogenic?

DSG2 p.Val987Phe (c.2959G>T) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.2134); Ultra-rare (popmax 0.0914%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Val987Phe (c.2959G>T)?

DSG2 p.Val987Phe (c.2959G>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Val987Phe (c.2959G>T) in the general population?

DSG2 p.Val987Phe (c.2959G>T) is ultra-rare (popmax 0.0914%, eas) (gnomAD).

What do computational predictors say about DSG2 p.Val987Phe (c.2959G>T)?

AlphaMissense predicts likely benign (score 0.2134) — an in-silico prediction, not a clinical call.

DSG2 p.Val987Phe

c.2959G>T · rs141405267 · VCV520438

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2134 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0914%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2134	likely benign
REVEL	0.487	indeterminate
SaProt	LLR -9.79	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 5.8	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	23.1	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 0.0914% East Asian · 41/44,848 alleles

Filtering AF 0.0692% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0614%

Overall 0.00279% 45/1,612,854 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0914%	1,094
Remaining individualsnot grpmax-eligible	0.0048%	20,819
South Asian	0.0011%	90,926

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.Val987Phe
Coding: c.2959G>T
MANE Select: NM_001943
dbSNP: rs141405267
Type: single nucleotide variant
Location: chr18:31546345 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 987: 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

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

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 10 arrhythmogenic right ventricular cardiomyopathy

Similar variants

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
DSG2 p.Arg46Trp 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-val987phe (accessed [today's date]).

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