Is CAD p.Arg2200His (c.6599G>A) pathogenic?

CAD p.Arg2200His (c.6599G>A) is classified Uncertain significance in CAD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.9702); Very rare (popmax 0.00159%, afr); Associated with Inborn genetic diseases.

What condition is associated with CAD p.Arg2200His (c.6599G>A)?

CAD p.Arg2200His (c.6599G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAD p.Arg2200His (c.6599G>A) in the general population?

CAD p.Arg2200His (c.6599G>A) is very rare (popmax 0.00159%, afr) (gnomAD).

What do computational predictors say about CAD p.Arg2200His (c.6599G>A)?

AlphaMissense predicts likely pathogenic (score 0.9702) — an in-silico prediction, not a clinical call.

CAD p.Arg2200His

c.6599G>A · VCV4218128

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9702 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00159%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9702	likely pathogenic
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -10.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 868 bp · p 0.0038 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00159% African / African-American · 1/63,052 alleles

Filtering AF 7.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.1e-05%

Overall 0.00028% 4/1,430,780 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00159%	63,052
European (non-Finnish)	0.000288%	346,806

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.Arg2200His
Coding: c.6599G>A
MANE Select: NM_004341
Type: single nucleotide variant
Location: chr2:27243439 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 2200: a UniProt-annotated variant site (in dee50; uncertain significance); the 'atcase (aspartate transcarbamylase)' 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 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
CAD p.Arg1075His Uncertain significance ★★ ⚠ same condition
CAD p.Arg1181Gln 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-arg2200his (accessed [today's date]).

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