Is CAD p.Val233Ile (c.697G>A) pathogenic?

CAD p.Val233Ile (c.697G>A) is classified Conflicting classifications of pathogenicity in CAD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-09-07). AlphaMissense: likely benign (0.0733); Ultra-rare (popmax 0.0557%, eas); Associated with Inborn genetic diseases.

What condition is associated with CAD p.Val233Ile (c.697G>A)?

CAD p.Val233Ile (c.697G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAD p.Val233Ile (c.697G>A) in the general population?

CAD p.Val233Ile (c.697G>A) is ultra-rare (popmax 0.0557%, eas) (gnomAD).

What do computational predictors say about CAD p.Val233Ile (c.697G>A)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

CAD p.Val233Ile

c.697G>A · rs146747331 · VCV1424350

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0557%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -6.88	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 6.7	GERP -0.39, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 5,475 bp · p 0.17 · regional, not allelic
Overall
CADD	14.83	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 0.0557% East Asian · 25/44,892 alleles

Filtering AF 0.0387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.00719% 116/1,613,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0557%	1,796
Middle Eastern	0.0164%	6,084
African / African-American	0.0107%	9,360
European (non-Finnish)	0.00644%	15,526
Remaining individualsnot grpmax-eligible	0.0064%	15,619
South Asian	0.0022%	45,541

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.Val233Ile
Coding: c.697G>A
MANE Select: NM_004341
dbSNP: rs146747331
Type: single nucleotide variant
Location: chr2:27222925 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 233: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAD p.Val233Leu Uncertain significance ★ ⚠ same residue
CAD p.Val233= Likely benign ★ same residue
CAD c.6480+6T>C Uncertain significance ★★ same condition
CAD p.Ala1527Thr Uncertain significance ★★ ⚠ same condition
CAD p.Ala1769Thr Uncertain significance ★★ ⚠ same condition
CAD p.Ala1824Ser Uncertain significance ★★ ⚠ same condition
CAD p.Ala495Pro Uncertain significance ★★ ⚠ same condition
CAD p.Ala608Thr 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-val233ile (accessed [today's date]).

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