Is CAD p.Ala1591= (c.4773A>G) pathogenic?

CAD p.Ala1591= (c.4773A>G) is classified Benign in CAD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 76.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with developmental and epileptic encephalopathy, 50.

What condition is associated with CAD p.Ala1591= (c.4773A>G)?

CAD p.Ala1591= (c.4773A>G) is associated with developmental and epileptic encephalopathy, 50 (ClinVar).

How is CAD-CDG inherited?

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

CAD p.Ala1591=

Q: How common is CAD p.Ala1591= (c.4773A>G) in the general population?

CAD p.Ala1591= (c.4773A>G) is common (popmax 76.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4773A>G · rs1141313 · VCV1192646

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 76.7%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

developmental and epileptic encephalopathy, 50

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.071	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP -3.8
Overall
CADD	0.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 76.7% African / African-American · 57,513/74,958 alleles

Filtering AF 76.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 76%

Overall 32.6% 525,515/1,613,914 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	76.7%	1
Admixed American	53.4%	2
Middle Eastern	40.1%	2
South Asian	39.6%	3
Ashkenazi Jewishnot grpmax-eligible	34.6%	3
Remaining individualsnot grpmax-eligible	34.4%	3
Amishnot grpmax-eligible	31.8%	3
European (non-Finnish)	29.1%	3
Finnishnot grpmax-eligible	24.9%	4
East Asian	12.5%	8

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.Ala1591=
Coding: c.4773A>G
MANE Select: NM_004341
dbSNP: rs1141313
Type: single nucleotide variant
Location: chr2:27238100 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 1591: the 'dhoase (dihydroorotase)' region

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.Ala1591Thr 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-ala1591 (accessed [today's date]).

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