Is CAST p.Arg550Cys (c.1648C>T) pathogenic?

CAST p.Arg550Cys (c.1648C>T) is classified Uncertain significance in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely benign (0.1122); Ultra-rare (popmax 0.0791%, afr).

How common is CAST p.Arg550Cys (c.1648C>T) in the general population?

CAST p.Arg550Cys (c.1648C>T) is ultra-rare (popmax 0.0791%, afr) (gnomAD).

What do computational predictors say about CAST p.Arg550Cys (c.1648C>T)?

AlphaMissense predicts likely benign (score 0.1122) — an in-silico prediction, not a clinical call.

CAST p.Arg550Cys

c.1648C>T · VCV3384355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1122 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0791%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1122	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -10.51	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -1.3
Overall
CADD	23.4	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 R467C vs ClinVar R550C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0791% African / African-American · 59/74,576 alleles

Filtering AF 0.0629% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0571%

Overall 0.0232% 373/1,606,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0791%	1,264
European (non-Finnish)	0.0244%	4,093
Remaining individualsnot grpmax-eligible	0.0193%	5,185
Finnishnot grpmax-eligible	0.0125%	7,991
Admixed American	0.00838%	11,927
South Asian	0.00221%	45,225

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.Arg550Cys
Coding: c.1648C>T
Type: single nucleotide variant
Location: chr5:96754679 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 550: the 'disordered' region

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

Similar variants

PCSK1 p.Asn550= Benign/Likely benign ★★ same residue
CAST p.Arg550Gly Uncertain significance ★ ⚠ same residue
CAST p.Arg550His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg550cys (accessed [today's date]).

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