Is CAST p.Arg461Gln (c.1382G>A) pathogenic?

CAST p.Arg461Gln (c.1382G>A) is classified Likely benign in CAST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely benign (0.071); Ultra-rare (popmax 0.0713%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Arg461Gln (c.1382G>A)?

CAST p.Arg461Gln (c.1382G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Arg461Gln (c.1382G>A) in the general population?

CAST p.Arg461Gln (c.1382G>A) is ultra-rare (popmax 0.0713%, afr) (gnomAD).

What do computational predictors say about CAST p.Arg461Gln (c.1382G>A)?

AlphaMissense predicts likely benign (score 0.071) — an in-silico prediction, not a clinical call.

CAST p.Arg461Gln

c.1382G>A · rs142513839 · VCV2241251

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0713%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.071	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -6.47	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 -8.3	GERP -5.5
Overall
CADD	0.002	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 R378Q vs ClinVar R461Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0713% African / African-American · 53/74,324 alleles

Filtering AF 0.0559% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0505%

Overall 0.00442% 70/1,585,450 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0713%	1,402
Remaining individualsnot grpmax-eligible	0.00488%	20,500
East Asian	0.00448%	22,341
Admixed American	0.00334%	29,925
South Asian	0.00222%	45,138
Finnishnot grpmax-eligible	0.00156%	63,936
European (non-Finnish)	0.000606%	164,933

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.Arg461Gln
Coding: c.1382G>A
dbSNP: rs142513839
Type: single nucleotide variant
Location: chr5:96748567 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 461: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAST p.Arg461Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CAST p.Arg461Trp Uncertain significance ★ ⚠ same residue
CAST p.Ala329Gly Uncertain significance ★★ ⚠ same condition
CAST p.Asp160Val Uncertain significance ★★ ⚠ same condition
CAST p.Gln731His Uncertain significance ★★ ⚠ same condition
CAST p.Glu296Gly Uncertain significance ★★ ⚠ same condition
CAST p.Ile274Val Uncertain significance ★★ ⚠ same condition
CAST p.Leu586Pro 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-arg461gln (accessed [today's date]).

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