Is CSTA p.Lys22Ter (c.64A>T) pathogenic?

CSTA p.Lys22Ter (c.64A>T) is classified Pathogenic in CSTA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-12). Ultra-rare (popmax 0.0164%, mid); Associated with peeling skin syndrome 4.

What condition is associated with CSTA p.Lys22Ter (c.64A>T)?

CSTA p.Lys22Ter (c.64A>T) is associated with peeling skin syndrome 4 (ClinVar).

How common is CSTA p.Lys22Ter (c.64A>T) in the general population?

CSTA p.Lys22Ter (c.64A>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Exfoliative ichthyosis inherited?

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

CSTA p.Lys22Ter

c.64A>T · rs747711488 · VCV208472

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

peeling skin syndrome 4

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 3
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -4.1
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00279% 45/1,614,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.00347%	28,780
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Admixed American	0.00167%	60,010

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: CSTA
Protein: p.Lys22Ter
Coding: c.64A>T
MANE Select: NM_005213
dbSNP: rs747711488
Type: single nucleotide variant
Location: chr3:122325356 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI 0.12 (gnomAD)
Structure: AlphaFold pLDDT 93.57 · 14 PDB
Residue 22: an α-helix

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

Disease context

peeling skin syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Exfoliative ichthyosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CSTA p.Arg58Ter Likely pathogenic ★★ same condition
CSTA c.67-2A>T Pathogenic ★ same condition
CSTA p.Tyr35Ter Likely pathogenic ★ same condition
CSTA p.Gln86Ter Pathogenic same condition
CSTA c.169-12A>C Benign ★★ same type
CSTA p.Lys91Asn Benign ★★ ⚠ same type
CSTA p.Thr96Met Benign ★★ ⚠ same type
CSTA p.Tyr35= Benign ★★ same type

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/csta-p-lys22ter (accessed [today's date]).

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