Is CAST p.Ala403Pro (c.1207G>C) pathogenic?

CAST p.Ala403Pro (c.1207G>C) is classified Benign in CAST (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-25). AlphaMissense: ambiguous (0.4941); Common (popmax 5.18%, afr) — too common for a highly-penetrant pathogenic allele; Associated with peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome.

What do computational predictors say about CAST p.Ala403Pro (c.1207G>C)?

AlphaMissense predicts ambiguous (score 0.4941) — an in-silico prediction, not a clinical call.

CAST p.Ala403Pro

Q: What condition is associated with CAST p.Ala403Pro (c.1207G>C)?

CAST p.Ala403Pro (c.1207G>C) is associated with peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (ClinVar).

Q: How common is CAST p.Ala403Pro (c.1207G>C) in the general population?

CAST p.Ala403Pro (c.1207G>C) is common (popmax 5.18%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1207G>C · rs76738700 · VCV791137

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4941 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.18%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.4941	ambiguous · top 7% in CAST
REVEL	0.35	indeterminate
SaProt	LLR -8.18	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.47	GERP -3.5, phastCons 0.99
Overall
CADD	21.1	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 A320P vs ClinVar A403P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.18% African / African-American · 3,870/74,710 alleles

Filtering AF 5.04% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.99%

Overall 0.269% 4,319/1,602,796 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.18%	19
Remaining individualsnot grpmax-eligible	0.369%	271
Admixed American	0.28%	357
Middle Eastern	0.149%	671
South Asian	0.0121%	8,261
European (non-Finnish)	0.00274%	36,557

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.Ala403Pro
Coding: c.1207G>C
dbSNP: rs76738700
Type: single nucleotide variant
Location: chr5:96746348 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 403: 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.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
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-ala403pro (accessed [today's date]).

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