Is CAST p.Asp414Glu (c.1242T>A) pathogenic?

CAST p.Asp414Glu (c.1242T>A) is classified Benign in CAST (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.2583); Low-frequency (popmax 1.14%, afr).

How common is CAST p.Asp414Glu (c.1242T>A) in the general population?

CAST p.Asp414Glu (c.1242T>A) is low-frequency (popmax 1.14%, afr) (gnomAD).

What do computational predictors say about CAST p.Asp414Glu (c.1242T>A)?

AlphaMissense predicts likely benign (score 0.2583) — an in-silico prediction, not a clinical call.

CAST p.Asp414Glu

c.1242T>A · rs112593332 · VCV711433

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2583 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.14%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2583	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -5.14	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 -0.35	GERP 1.5, phastCons 0.34
Overall
CADD	19.45	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 D331E vs ClinVar D414E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.14% African / African-American · 852/75,016 alleles

Filtering AF 1.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.05%

Overall 0.0592% 955/1,612,968 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.14%	88
Middle Eastern	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0784%	1,275
Admixed American	0.065%	1,539
South Asian	0.00549%	18,214
European (non-Finnish)	0.000339%	294,728

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.Asp414Glu
Coding: c.1242T>A
dbSNP: rs112593332
Type: single nucleotide variant
Location: chr5:96746383 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67

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

Similar variants

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
CAST p.Ser231Leu 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-asp414glu (accessed [today's date]).

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