Is CDSN p.Leu509= (c.1525C>T) pathogenic?

CDSN p.Leu509= (c.1525C>T) is classified Benign/Likely benign in CDSN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-01). Rare (popmax 0.164%, nfe); Associated with hypotrichosis 2.

What condition is associated with CDSN p.Leu509= (c.1525C>T)?

CDSN p.Leu509= (c.1525C>T) is associated with hypotrichosis 2, peeling skin syndrome 1 (ClinVar).

How common is CDSN p.Leu509= (c.1525C>T) in the general population?

CDSN p.Leu509= (c.1525C>T) is rare (popmax 0.164%, nfe) (gnomAD).

How is Hypotrichosis simplex of the scalp inherited?

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

CDSN p.Leu509=

c.1525C>T · rs150958659 · VCV716000

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.164%, nfe)

Conditions

hypotrichosis 2

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 2.1	phastCons 0.99
Overall
CADD	6.348	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.164% European (non-Finnish) · 1,931/1,179,556 alleles

Filtering AF 0.158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.155%

Overall 0.17% 2,740/1,612,108 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.979%	102
European (non-Finnish)grpmax	0.164%	611
Remaining individualsnot grpmax-eligible	0.119%	844
Ashkenazi Jewishnot grpmax-eligible	0.088%	1,136
Middle Eastern	0.0685%	1,461
Admixed American	0.0617%	1,622
South Asian	0.0396%	2,528
African / African-American	0.0213%	4,690

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CDSN
Protein: p.Leu509=
Coding: c.1525C>T
MANE Select: NM_001264
dbSNP: rs150958659
Type: single nucleotide variant
Location: chr6:31116090 (GRCh38)
Gene constraint: LOEUF 0.77 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 38.13

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

Disease context

hypotrichosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: peeling skin syndrome 1

For Hypotrichosis simplex of the scalp (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

Similar variants

CDSN p.Leu509Pro Likely benign ★ same residue
CDSN p.Lys59Ter Pathogenic ★★ same condition
CDSN p.Pro447Leu Uncertain significance ★★ same condition
CDSN p.Asn179Ser Likely benign ★★ same condition
CDSN p.Asn527Asp Benign ★★ same condition
CDSN p.Ser453Asn Benign ★★ same condition
CDSN p.Gln162Ter Likely pathogenic ★ same condition
CDSN p.Gly487Ser Likely pathogenic ★ 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/cdsn-p-leu509 (accessed [today's date]).

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