Is CAST p.Lys183Ter (c.547A>T) pathogenic?

CAST p.Lys183Ter (c.547A>T) is classified Pathogenic in CAST (ClinVar, No assertion criteria, 1 submitter; last evaluated 2015-03-05). Absent from gnomAD v4.1; Associated with peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome.

How common is CAST p.Lys183Ter (c.547A>T) in the general population?

CAST p.Lys183Ter (c.547A>T) is absent from gnomAD v4.1 (gnomAD).

CAST p.Lys183Ter

Q: What condition is associated with CAST p.Lys183Ter (c.547A>T)?

CAST p.Lys183Ter (c.547A>T) is associated with peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (ClinVar).

Q: How is Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome inherited?

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

c.547A>T · rs786204842 · VCV189335

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

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-escape possible for C-terminal truncations
REVEL	0.014	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1.6, phastCons 1
Overall
CADD	36.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAST
Protein: p.Lys183Ter
Coding: c.547A>T
dbSNP: rs786204842
Type: single nucleotide variant
Location: chr5:96729723 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 183: the 'disordered' region

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

Disease context

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CAST c.1525-106G>A Benign ★★ same condition
CAST p.Ala403Pro Benign ★★ same condition
CAST p.Ala481Thr Benign ★★ same condition
CAST p.Cys491Ser Benign ★★ same condition
CAST p.Gln56= Benign ★★ same condition
CAST c.630+1G>T Likely pathogenic ★ same condition
CAST c.630+2T>C Likely pathogenic ★ same condition
CAST p.Gln628Ter 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/cast-p-lys183ter (accessed [today's date]).

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