Is CAD p.Val662Ile (c.1984G>A) pathogenic?

CAD p.Val662Ile (c.1984G>A) is classified Uncertain significance in CAD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-08-10). AlphaMissense: likely benign (0.087); Ultra-rare (popmax 0.0375%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CAD p.Val662Ile (c.1984G>A)?

CAD p.Val662Ile (c.1984G>A) is associated with Inborn genetic diseases, developmental and epileptic encephalopathy, 50 (ClinVar).

How common is CAD p.Val662Ile (c.1984G>A) in the general population?

CAD p.Val662Ile (c.1984G>A) is ultra-rare (popmax 0.0375%, nfe) (gnomAD).

What do computational predictors say about CAD p.Val662Ile (c.1984G>A)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

CAD p.Val662Ile

c.1984G>A · rs147722428 · VCV1343588

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0375%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.87, phastCons 0.96
Regional constraint	o/e 0.72	unconstrained · MANE · 7,481 bp · p 8.7e-11 · regional, not allelic
Overall
CADD	16.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0375% European (non-Finnish) · 442/1,180,042 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0334%

Overall 0.0281% 454/1,614,112 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0375%	2,670
Remaining individualsnot grpmax-eligible	0.0112%	8,927
African / African-American	0.004%	24,979
Finnishnot grpmax-eligible	0.00156%	64,042
South Asian	0.0011%	91,094

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.Val662Ile
Coding: c.1984G>A
MANE Select: NM_004341
dbSNP: rs147722428
Type: single nucleotide variant
Location: chr2:27226272 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 662: the atp-grasp 1 domain; the 'cpsase (carbamoyl phosphate synthase)' region; the 'cpsase a' region

Full CAD 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

Also linked: developmental and epileptic encephalopathy, 50

Similar variants

CAD p.Val662Phe 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.6480+6T>C 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-val662ile (accessed [today's date]).

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