Is DSG4 p.Ser165= (c.495C>T) pathogenic?

DSG4 p.Ser165= (c.495C>T) is classified Benign in DSG4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 96.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hypotrichosis 6.

What condition is associated with DSG4 p.Ser165= (c.495C>T)?

DSG4 p.Ser165= (c.495C>T) is associated with hypotrichosis 6 (ClinVar).

How is Hypotrichosis simplex inherited?

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

DSG4 p.Ser165=

Q: How common is DSG4 p.Ser165= (c.495C>T) in the general population?

DSG4 p.Ser165= (c.495C>T) is common (popmax 96.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.495C>T · rs9956865 · VCV326421

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 96.4%, eas) — too common for a highly-penetrant pathogenic allele

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 0.55	GERP -3.9, phastCons 0.95
Overall
CADD	6.749	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 96.4% East Asian · 43,212/44,836 alleles

Filtering AF 95.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 95.3%

Overall 76.2% 1,226,942/1,611,094 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	96.4%	1
Admixed American	88.5%	1
Middle Eastern	84%	1
Amishnot grpmax-eligible	81.9%	1
African / African-American	81.5%	1
Remaining individualsnot grpmax-eligible	76.5%	1
Ashkenazi Jewishnot grpmax-eligible	76%	1
European (non-Finnish)	75.3%	1
Finnishnot grpmax-eligible	70.3%	1
South Asian	67.8%	1

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.Ser165=
Coding: c.495C>T
dbSNP: rs9956865
Type: single nucleotide variant
Location: chr18:31388996 (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-ser165 (accessed [today's date]).

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