Is CAST p.Ala481Thr (c.1441G>A) pathogenic?

CAST p.Ala481Thr (c.1441G>A) is classified Benign in CAST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-03-29). AlphaMissense: likely benign (0.0708); Rare (popmax 0.722%, sas); Associated with peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome.

How common is CAST p.Ala481Thr (c.1441G>A) in the general population?

CAST p.Ala481Thr (c.1441G>A) is rare (popmax 0.722%, sas) (gnomAD).

What do computational predictors say about CAST p.Ala481Thr (c.1441G>A)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

CAST p.Ala481Thr

Q: What condition is associated with CAST p.Ala481Thr (c.1441G>A)?

CAST p.Ala481Thr (c.1441G>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.1441G>A · rs546937644 · VCV1614516

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.722%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -6.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.89	GERP -5.2
Overall
CADD	3.857	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A398T vs ClinVar A481T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.722% South Asian · 657/91,032 alleles

Filtering AF 0.676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.658%

Overall 0.0447% 720/1,611,628 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.722%	139
Middle Eastern	0.0827%	1,210
Remaining individualsnot grpmax-eligible	0.0417%	2,400
European (non-Finnish)	0.00272%	36,820

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.Ala481Thr
Coding: c.1441G>A
dbSNP: rs546937644
Type: single nucleotide variant
Location: chr5:96750599 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 481: 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.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
CAST p.Gln97Ter 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-ala481thr (accessed [today's date]).

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