Is CAD p.Arg2214His (c.6641G>A) pathogenic?

CAD p.Arg2214His (c.6641G>A) is classified Uncertain significance in CAD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-17). AlphaMissense: likely pathogenic (0.9915); Very rare (popmax 0.00462%, eas).

How common is CAD p.Arg2214His (c.6641G>A) in the general population?

CAD p.Arg2214His (c.6641G>A) is very rare (popmax 0.00462%, eas) (gnomAD).

What do computational predictors say about CAD p.Arg2214His (c.6641G>A)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

CAD p.Arg2214His

c.6641G>A · rs1368964042 · VCV1426652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00462%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic · top 8% in CAD
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -14.13	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 0.00462% East Asian · 2/43,274 alleles

Filtering AF 0.000766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000287%

Overall 0.000414% 6/1,447,798 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00462%	21,637
South Asian	0.00112%	89,384
European (non-Finnish)	0.000256%	390,360

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.Arg2214His
Coding: c.6641G>A
MANE Select: NM_004341
dbSNP: rs1368964042
Type: single nucleotide variant
Location: chr2:27243481 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 2214: a UniProt-annotated variant site (in dee50; uncertain significance); the 'atcase (aspartate transcarbamylase)' region; an α-helix

Full CAD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAD p.Arg2214Cys Uncertain significance ★ same residue
CAD p.Arg1789Ter Pathogenic ★★ same type
CAD p.Arg1810Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
CAD p.Arg191Ter Pathogenic ★★ same type
CAD p.Gln1604Ter Likely pathogenic ★★ same type
CAD p.Met33Arg Pathogenic ★★ same type
CAD c.1254+6G>A Uncertain significance ★★ same type
CAD c.2032-3C>T Uncertain significance ★★ same type

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-arg2214his (accessed [today's date]).

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