Is CAST p.Gln628Ter (c.1882C>T) pathogenic?

CAST p.Gln628Ter (c.1882C>T) is classified Likely pathogenic in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-01). Absent from gnomAD v4.1; Associated with peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome.

How common is CAST p.Gln628Ter (c.1882C>T) in the general population?

CAST p.Gln628Ter (c.1882C>T) is absent from gnomAD v4.1 (gnomAD).

CAST p.Gln628Ter

Q: What condition is associated with CAST p.Gln628Ter (c.1882C>T)?

CAST p.Gln628Ter (c.1882C>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.1882C>T · VCV4076958

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

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	0.045	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP 2.1, phastCons 0.11
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.Gln628Ter
Coding: c.1882C>T
Type: single nucleotide variant
Location: chr5:96762322 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 628: 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

PCSK1 p.Glu628Lys Uncertain significance ★ ⚠ same residue
PCSK1 p.Glu628Asp Uncertain significance ⚠ same residue
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

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-gln628ter (accessed [today's date]).

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