Is CAST p.Glu224Asp (c.672A>C) pathogenic?

CAST p.Glu224Asp (c.672A>C) is classified Conflicting classifications of pathogenicity in CAST (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-10). AlphaMissense: likely benign (0.0871); Rare (popmax 0.305%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAST p.Glu224Asp (c.672A>C)?

CAST p.Glu224Asp (c.672A>C) is associated with Inborn genetic diseases (ClinVar).

How common is CAST p.Glu224Asp (c.672A>C) in the general population?

CAST p.Glu224Asp (c.672A>C) is rare (popmax 0.305%, afr) (gnomAD).

What do computational predictors say about CAST p.Glu224Asp (c.672A>C)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

CAST p.Glu224Asp

c.672A>C · rs143382715 · VCV2864530

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.305%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.98	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 1.1	GERP -2.8, phastCons 0.06
Overall
CADD	14.41	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 E141D vs ClinVar E224D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.305% African / African-American · 229/74,976 alleles

Filtering AF 0.273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.26%

Overall 0.0177% 286/1,612,752 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.305%	327
Remaining individualsnot grpmax-eligible	0.0336%	2,974
Admixed American	0.0317%	3,156
Middle Eastern	0.0165%	6,058
South Asian	0.00659%	15,164
European (non-Finnish)	0.000848%	117,917

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.Glu224Asp
Coding: c.672A>C
dbSNP: rs143382715
Type: single nucleotide variant
Location: chr5:96736213 (GRCh38)
Gene constraint: LOEUF 1.208 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 59.67
Residue 224: 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-glu224asp (accessed [today's date]).

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