Is CAD p.Ala1532= (c.4596G>A) pathogenic?

CAD p.Ala1532= (c.4596G>A) is classified Benign/Likely benign in CAD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-31). Low-frequency (popmax 2.05%, afr); Associated with developmental and epileptic encephalopathy, 50.

What condition is associated with CAD p.Ala1532= (c.4596G>A)?

CAD p.Ala1532= (c.4596G>A) is associated with developmental and epileptic encephalopathy, 50 (ClinVar).

How common is CAD p.Ala1532= (c.4596G>A) in the general population?

CAD p.Ala1532= (c.4596G>A) is low-frequency (popmax 2.05%, afr) (gnomAD).

How is CAD-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

CAD p.Ala1532=

c.4596G>A · rs151204610 · VCV786478

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.05%, afr)

Conditions

developmental and epileptic encephalopathy, 50

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.079	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.001	GERP -2.6, phastCons 0.48
Overall
CADD	8.272	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.05% African / African-American · 1,536/75,058 alleles

Filtering AF 1.96% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.93%

Overall 0.124% 2,009/1,614,114 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.05%	49
Remaining individualsnot grpmax-eligible	0.238%	419
Admixed American	0.233%	429
Middle Eastern	0.099%	1,010
European (non-Finnish)	0.0142%	7,024
South Asian	0.00988%	10,118
East Asian	0.00223%	44,886

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: CAD
Protein: p.Ala1532=
Coding: c.4596G>A
MANE Select: NM_004341
dbSNP: rs151204610
Type: single nucleotide variant
Location: chr2:27237750 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 1532: the 'dhoase (dihydroorotase)' region; a β-strand

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

Disease context

developmental and epileptic encephalopathy, 50 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CAD-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CAD p.Ala1532Val Uncertain significance ★ ⚠ same residue
CAD p.Arg1789Ter Pathogenic ★★ same condition
CAD p.Arg1810Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
CAD p.Arg191Ter Pathogenic ★★ same condition
CAD p.Gln1604Ter Likely pathogenic ★★ same condition
CAD p.Met33Arg Pathogenic ★★ same condition
CAD c.4315-3C>T Uncertain significance ★★ same condition
CAD c.996-13A>G 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/cad-p-ala1532 (accessed [today's date]).

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