Is CAST p.Thr428= (c.1284G>A) pathogenic?

CAST p.Thr428= (c.1284G>A) is classified Uncertain significance in CAST (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-26). Ultra-rare (popmax 0.058%, nfe); Associated with peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome.

How common is CAST p.Thr428= (c.1284G>A) in the general population?

CAST p.Thr428= (c.1284G>A) is ultra-rare (popmax 0.058%, nfe) (gnomAD).

CAST p.Thr428=

Q: What condition is associated with CAST p.Thr428= (c.1284G>A)?

CAST p.Thr428= (c.1284G>A) 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.1284G>A · VCV3592841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.058%, nfe)

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/SpliceAI carries the signal.
REVEL	0.273	benign-leaning
Splicing
SpliceAI	Δ0.94	donor loss · deltas
Pangolin	Δ0.79	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.3	GERP 0.91, phastCons 0.34
Overall
CADD	17.35	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.058% European (non-Finnish) · 670/1,156,090 alleles

Filtering AF 0.0543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0529%

Overall 0.0442% 701/1,587,686 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.058%	1,726
Remaining individualsnot grpmax-eligible	0.0308%	3,243
African / African-American	0.0108%	9,282
Admixed American	0.005%	19,984
South Asian	0.0011%	90,530

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: CAST
Protein: p.Thr428=
Coding: c.1284G>A
Type: single nucleotide variant
Location: chr5:96746425 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 428: 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 p.Thr428Met Benign ★★ 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
CAST c.630+2T>C 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-thr428 (accessed [today's date]).

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