Is DSG4 p.Pro267Arg (c.800C>G) pathogenic?

DSG4 p.Pro267Arg (c.800C>G) is classified Pathogenic in DSG4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2006-06-01). AlphaMissense: likely pathogenic (0.9868); Ultra-rare (popmax 0.0165%, mid); Associated with hypotrichosis 6.

What condition is associated with DSG4 p.Pro267Arg (c.800C>G)?

DSG4 p.Pro267Arg (c.800C>G) is associated with hypotrichosis 6 (ClinVar).

How common is DSG4 p.Pro267Arg (c.800C>G) in the general population?

DSG4 p.Pro267Arg (c.800C>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Hypotrichosis simplex inherited?

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

What do computational predictors say about DSG4 p.Pro267Arg (c.800C>G)?

AlphaMissense predicts likely pathogenic (score 0.9868) — an in-silico prediction, not a clinical call.

DSG4 p.Pro267Arg

c.800C>G · rs267606776 · VCV2724

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9868 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypotrichosis 6

Computational evidence

Protein change
AlphaMissense	0.9868	likely pathogenic ✓ concordant with ClinVar
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -13.63	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 37 kb · p 0.015 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,058 alleles

Overall 0.000205% 3/1,461,326 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.0032%	31,237

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.Pro267Arg
Coding: c.800C>G
dbSNP: rs267606776
Type: single nucleotide variant
Location: chr18:31391193 (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-pro267arg (accessed [today's date]).

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