Is DSG4 p.Arg74Pro (c.221G>C) pathogenic?

DSG4 p.Arg74Pro (c.221G>C) is classified Uncertain significance in DSG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.9879); Ultra-rare (popmax 0.0121%, sas); Associated with Inborn genetic diseases.

What condition is associated with DSG4 p.Arg74Pro (c.221G>C)?

DSG4 p.Arg74Pro (c.221G>C) is associated with Inborn genetic diseases (ClinVar).

How common is DSG4 p.Arg74Pro (c.221G>C) in the general population?

DSG4 p.Arg74Pro (c.221G>C) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about DSG4 p.Arg74Pro (c.221G>C)?

AlphaMissense predicts likely pathogenic (score 0.9879) — an in-silico prediction, not a clinical call.

DSG4 p.Arg74Pro

c.221G>C · VCV4245095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9879 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9879	likely pathogenic · top 4% in DSG4
REVEL	0.34	indeterminate
SaProt	LLR -12.95	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 37 kb · p 0.015 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0121% South Asian · 11/91,044 alleles

Filtering AF 0.00677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.000868% 14/1,612,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,277
European (non-Finnish)	0.000254%	393,113

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.Arg74Pro
Coding: c.221G>C
MANE Select: NM_177986
Type: single nucleotide variant
Location: chr18:31388371 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.63
Residue 74: the cadherin 1 domain

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

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DSG4 p.His902Arg Uncertain significance ★★ ⚠ same condition
DSG4 p.Tyr585His 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
DSG4 p.Thr1020Ile 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-arg74pro (accessed [today's date]).

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