Is DSG4 p.Arg967= (c.2901A>G) pathogenic?

DSG4 p.Arg967= (c.2901A>G) is classified Conflicting classifications of pathogenicity in DSG4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-04). Rare (popmax 0.397%, afr); Associated with hypotrichosis 6.

What condition is associated with DSG4 p.Arg967= (c.2901A>G)?

DSG4 p.Arg967= (c.2901A>G) is associated with hypotrichosis 6 (ClinVar).

How common is DSG4 p.Arg967= (c.2901A>G) in the general population?

DSG4 p.Arg967= (c.2901A>G) is rare (popmax 0.397%, afr) (gnomAD).

How is Hypotrichosis simplex inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DSG4 p.Arg967=

c.2901A>G · rs151254406 · VCV784547

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.397%, afr)

Conditions

hypotrichosis 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -2.2, phastCons 1
Overall
CADD	6.717	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.397% African / African-American · 298/75,018 alleles

Filtering AF 0.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.346%

Overall 0.0226% 364/1,614,170 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.397%	252
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0432%	2,315
Admixed American	0.0233%	4,288
European (non-Finnish)	0.00161%	62,108
Finnishnot grpmax-eligible	0.00156%	64,032
South Asian	0.0011%	91,084

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.Arg967=
Coding: c.2901A>G
MANE Select: NM_177986
dbSNP: rs151254406
Type: single nucleotide variant
Location: chr18:31413373 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.63
Residue 967: a UniProt-annotated variant site (in hypt6; significant decrease in interaction with jup and localization to desmosomes)

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

Disease context

hypotrichosis 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypotrichosis simplex (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood

Similar variants

DSG4 p.His386Gln Uncertain significance ★★ ⚠ same condition
DSG4 p.His902Arg Uncertain significance ★★ ⚠ same condition
DSG4 p.Tyr585His Uncertain significance ★★ ⚠ same condition
DSG4 c.*126G>A Benign/Likely benign ★★ same condition
DSG4 c.*31C>T Benign ★★ same condition
DSG4 p.Ala154Thr Benign/Likely benign ★★ ⚠ same condition
DSG4 p.Ile439Thr Benign/Likely benign ★★ ⚠ same condition
DSG4 p.Met1023Ile Benign/Likely benign ★★ 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-arg967 (accessed [today's date]).

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