Is DSG4 p.Val376= (c.1128T>C) pathogenic?

DSG4 p.Val376= (c.1128T>C) is classified Conflicting classifications of pathogenicity in DSG4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-20). Rare (popmax 0.568%, amr); Associated with hypotrichosis 6.

What condition is associated with DSG4 p.Val376= (c.1128T>C)?

DSG4 p.Val376= (c.1128T>C) is associated with hypotrichosis 6 (ClinVar).

How common is DSG4 p.Val376= (c.1128T>C) in the general population?

DSG4 p.Val376= (c.1128T>C) is rare (popmax 0.568%, amr) (gnomAD).

How is Hypotrichosis simplex inherited?

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

DSG4 p.Val376=

c.1128T>C · rs143590546 · VCV711703

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.568%, amr)

Conditions

hypotrichosis 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.98	GERP -2.2, phastCons 0.79
Overall
CADD	3.201	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.568% Admixed American · 341/60,020 alleles

Filtering AF 0.518% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.499%

Overall 0.22% 3,551/1,614,126 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.568%	176
European (non-Finnish)	0.255%	393
Remaining individualsnot grpmax-eligible	0.242%	414
Middle Eastern	0.099%	1,010
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,960
African / African-American	0.0293%	3,411
Finnishnot grpmax-eligible	0.0219%	4,574
South Asian	0.0011%	91,082

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.Val376=
Coding: c.1128T>C
dbSNP: rs143590546
Type: single nucleotide variant
Location: chr18:31399394 (GRCh38)

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

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-val376 (accessed [today's date]).

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