Is DSG4 p.Ser192Pro (c.574T>C) pathogenic?

DSG4 p.Ser192Pro (c.574T>C) is classified Pathogenic in DSG4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2006-06-01). AlphaMissense: likely pathogenic (0.9968); Ultra-rare (popmax 0.0134%, eas); Associated with hypotrichosis 6.

What condition is associated with DSG4 p.Ser192Pro (c.574T>C)?

DSG4 p.Ser192Pro (c.574T>C) is associated with hypotrichosis 6 (ClinVar).

How common is DSG4 p.Ser192Pro (c.574T>C) in the general population?

DSG4 p.Ser192Pro (c.574T>C) is ultra-rare (popmax 0.0134%, eas) (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.Ser192Pro (c.574T>C)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

DSG4 p.Ser192Pro

c.574T>C · rs267606775 · VCV2721

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypotrichosis 6

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic ✓ concordant with ClinVar · top 1% in DSG4
REVEL	0.567	indeterminate
SaProt	LLR -13.54	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 7.9	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 37 kb · p 0.015 · regional, not allelic
Overall
CADD	26.4	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 0.0134% East Asian · 6/44,860 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000372% 6/1,613,632 alleles · ultra-rare

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.Ser192Pro
Coding: c.574T>C
MANE Select: NM_177986
dbSNP: rs267606775
Type: single nucleotide variant
Location: chr18:31390712 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.63
Residue 192: a UniProt-annotated variant site (in hypt6); the cadherin 2 domain

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-ser192pro (accessed [today's date]).

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