Is CAD p.Arg287Cys (c.859C>T) pathogenic?

CAD p.Arg287Cys (c.859C>T) is classified Uncertain significance in CAD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-13). AlphaMissense: likely benign (0.2172); Ultra-rare (popmax 0.0174%, mid); Associated with developmental and epileptic encephalopathy, 50.

What condition is associated with CAD p.Arg287Cys (c.859C>T)?

CAD p.Arg287Cys (c.859C>T) is associated with developmental and epileptic encephalopathy, 50 (ClinVar).

How common is CAD p.Arg287Cys (c.859C>T) in the general population?

CAD p.Arg287Cys (c.859C>T) is ultra-rare (popmax 0.0174%, mid) (gnomAD).

How is CAD-CDG inherited?

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

What do computational predictors say about CAD p.Arg287Cys (c.859C>T)?

AlphaMissense predicts likely benign (score 0.2172) — an in-silico prediction, not a clinical call.

CAD p.Arg287Cys

c.859C>T · rs753478495 · VCV1028734

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2172 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 50

Computational evidence

Protein change
AlphaMissense	0.2172	likely benign
REVEL	0.931	moderately pathogenic-leaning
SaProt	LLR -11.45	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 825 bp · p 0.23 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0174% Middle Eastern · 1/5,750 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00198% 32/1,613,564 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0174%	5,750
Admixed American	0.005%	20,001
South Asian	0.00439%	22,762
Remaining individualsnot grpmax-eligible	0.0032%	31,229
East Asian	0.00223%	44,886
European (non-Finnish)	0.00178%	56,192

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.Arg287Cys
Coding: c.859C>T
MANE Select: NM_004341
dbSNP: rs753478495
Type: single nucleotide variant
Location: chr2:27223612 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 287: the glutamine amidotransferase type-1 domain; the 'gatase (glutamine amidotransferase)' 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.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
CAD c.996-4A>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-arg287cys (accessed [today's date]).

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