Is CAD p.Arg2174Trp (c.6520C>T) pathogenic?

CAD p.Arg2174Trp (c.6520C>T) is classified Uncertain significance in CAD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely benign (0.1447); Very rare (popmax 0.000254%, nfe).

How common is CAD p.Arg2174Trp (c.6520C>T) in the general population?

CAD p.Arg2174Trp (c.6520C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CAD p.Arg2174Trp (c.6520C>T)?

AlphaMissense predicts likely benign (score 0.1447) — an in-silico prediction, not a clinical call.

CAD p.Arg2174Trp

c.6520C>T · rs372558030 · VCV2186303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1447 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1447	likely benign
REVEL	0.646	pathogenic-leaning
SaProt	LLR -7.80	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 868 bp · p 0.0038 · regional, not allelic
Overall
CADD	25.6	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 0.000254% European (non-Finnish) · 3/1,180,004 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,842 alleles · very rare

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.Arg2174Trp
Coding: c.6520C>T
MANE Select: NM_004341
dbSNP: rs372558030
Type: single nucleotide variant
Location: chr2:27243237 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 2174: 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

Similar variants

CAD p.Arg2174Gln 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-arg2174trp (accessed [today's date]).

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