Is DSG4 p.Val528Ile (c.1582G>A) pathogenic?

DSG4 p.Val528Ile (c.1582G>A) is classified Uncertain significance in DSG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: likely benign (0.0863); Very rare (popmax 0.00347%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DSG4 p.Val528Ile (c.1582G>A)?

DSG4 p.Val528Ile (c.1582G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DSG4 p.Val528Ile (c.1582G>A) in the general population?

DSG4 p.Val528Ile (c.1582G>A) is very rare (popmax 0.00347%, nfe) (gnomAD).

What do computational predictors say about DSG4 p.Val528Ile (c.1582G>A)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

DSG4 p.Val528Ile

c.1582G>A · VCV4245087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00347%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0863	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -5.57	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 4.8	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 37 kb · p 0.015 · regional, not allelic
Overall
CADD	14.02	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 0.00347% European (non-Finnish) · 41/1,179,956 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00266% 43/1,613,888 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,779
African / African-American	0.00267%	37,452

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: DSG4
Protein: p.Val528Ile
Coding: c.1582G>A
MANE Select: NM_177986
Type: single nucleotide variant
Location: chr18:31403580 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.63

Full DSG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DSG4 p.His386Gln Uncertain significance ★★ ⚠ same condition
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DSG4 p.Tyr585His Uncertain significance ★★ ⚠ same condition
DSG4 p.Arg74Pro Uncertain significance ★ ⚠ same condition
DSG4 p.Cys576Arg Uncertain significance ★ ⚠ same condition
DSG4 p.Gly796Val Conflicting classifications of pathogenicity ★ ⚠ same condition
DSG4 p.Ser1008Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
DSG4 p.Ser897Cys Uncertain significance ★ ⚠ 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/dsg4-p-val528ile (accessed [today's date]).

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