Is CAST p.Ser487= (c.1461G>A) pathogenic?

CAST p.Ser487= (c.1461G>A) is classified Likely benign in CAST (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-07-25). Ultra-rare (popmax 0.033%, mid); Associated with CAST-related disorder.

What condition is associated with CAST p.Ser487= (c.1461G>A)?

CAST p.Ser487= (c.1461G>A) is associated with CAST-related disorder (ClinVar).

How common is CAST p.Ser487= (c.1461G>A) in the general population?

CAST p.Ser487= (c.1461G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

CAST p.Ser487=

c.1461G>A · rs371823208 · VCV3045722

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

CAST-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.01	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -5.2
Overall
CADD	0.349	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000992% 16/1,612,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.00641%	15,604
South Asian	0.00439%	22,762
African / African-American	0.00134%	74,802
European (non-Finnish)	0.000424%	235,867

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.Ser487=
Coding: c.1461G>A
dbSNP: rs371823208
Type: single nucleotide variant
Location: chr5:96750619 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 487: the 'disordered' region

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

Disease context

CAST-related disorder

Similar variants

PCSK1 p.Ala368Thr Uncertain significance ★★ ⚠ same condition
PCSK1 p.Asp193Gly Uncertain significance ★★ ⚠ same condition
CAST p.Gln499Ter Likely pathogenic ★ same condition
CAST p.Glu568Ter Likely pathogenic ★ same condition
PCSK1 p.Asn423Lys Likely pathogenic ★ same condition
PCSK1 p.Asn122Ser Uncertain significance ★ ⚠ same condition
PCSK1 p.Ile156Thr Uncertain significance ★ ⚠ same condition
PCSK1 p.Ile254Val Uncertain significance ★ ⚠ 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-ser487 (accessed [today's date]).

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