Is CAST p.Val221= (c.663G>T) pathogenic?

CAST p.Val221= (c.663G>T) is classified Benign in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-28). Common (popmax 8.23%, afr) — too common for a highly-penetrant pathogenic allele.

CAST p.Val221=

Q: How common is CAST p.Val221= (c.663G>T) in the general population?

CAST p.Val221= (c.663G>T) is common (popmax 8.23%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.663G>T · rs59522190 · VCV784053

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 8.23%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.014	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -3.3
Overall
CADD	1.666	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.23% African / African-American · 6,163/74,876 alleles

Filtering AF 8.06% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.99%

Overall 0.438% 7,068/1,612,732 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.23%	12
Admixed American	0.57%	175
Remaining individualsnot grpmax-eligible	0.543%	184
Middle Eastern	0.347%	288
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,466
European (non-Finnish)	0.0153%	6,552
South Asian	0.0121%	8,271

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.Val221=
Coding: c.663G>T
dbSNP: rs59522190
Type: single nucleotide variant
Location: chr5:96736204 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 221: the 'disordered' region

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

Similar variants

PCSK1 p.Asn221Asp Benign/Likely benign ★★ same residue
PCSK1 p.Lys286Ter Pathogenic/Likely pathogenic ★★ same type
CAST p.Ala329Gly Uncertain significance ★★ ⚠ same type
CAST p.Asp160Val Uncertain significance ★★ ⚠ same type
CAST p.Gln731His Uncertain significance ★★ ⚠ same type
CAST p.Glu296Gly Uncertain significance ★★ ⚠ same type
CAST p.Ile274Val Uncertain significance ★★ ⚠ same type
CAST p.Leu586Pro Uncertain significance ★★ ⚠ same type

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-val221 (accessed [today's date]).

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