Is CAST p.Asp458Val (c.1373A>T) pathogenic?

CAST p.Asp458Val (c.1373A>T) is classified Uncertain significance in CAST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: likely benign (0.2623); Ultra-rare (popmax 0.0215%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Asp458Val (c.1373A>T)?

CAST p.Asp458Val (c.1373A>T) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Asp458Val (c.1373A>T) in the general population?

CAST p.Asp458Val (c.1373A>T) is ultra-rare (popmax 0.0215%, afr) (gnomAD).

What do computational predictors say about CAST p.Asp458Val (c.1373A>T)?

AlphaMissense predicts likely benign (score 0.2623) — an in-silico prediction, not a clinical call.

CAST p.Asp458Val

c.1373A>T · rs781717789 · VCV2623369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2623 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0215%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2623	likely benign
REVEL	0.442	indeterminate
SaProt	LLR -8.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -2, phastCons 1
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D375V vs ClinVar D458V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0215% African / African-American · 16/74,390 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.011%

Overall 0.0012% 19/1,589,622 alleles · ultra-rare exomes 10/1,437,492 · genomes 9/152,130 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0215%	4,649
Remaining individualsnot grpmax-eligible	0.00325%	30,810
European (non-Finnish)	8.63e-05%	1,158,082

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.Asp458Val
Coding: c.1373A>T
dbSNP: rs781717789
Type: single nucleotide variant
Location: chr5:96748558 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 375 UniProt numbering: 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.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
CAST p.Ser231Leu Uncertain significance ★★ ⚠ same condition
PCSK1 p.Asp176Asn 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-asp458val (accessed [today's date]).

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