Is CAD p.Phe1766fs (c.5296_5308del) pathogenic?

CAD p.Phe1766fs (c.52965308del) is classified Pathogenic in CAD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-06). Very rare (popmax 0.004%, afr).

How common is CAD p.Phe1766fs (c.5296_5308del) in the general population?

CAD p.Phe1766fs (c.5296_5308del) is very rare (popmax 0.004%, afr) (gnomAD).

CAD p.Phe1766fs

c.5296_5308del · rs1019263242 · VCV430523

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 33 of 44
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 2, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,914 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00062% 10/1,613,936 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,971
European (non-Finnish)	0.000593%	168,566

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.Phe1766fs
Coding: c.5296_5308del
MANE Select: NM_004341
dbSNP: rs1019263242
Type: Deletion
Location: chr2:27239369 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 1766: the 'dhoase (dihydroorotase)' region

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

Similar variants

CAD p.Gly725fs Pathogenic/Likely pathogenic ★★ same type
CAD c.2401-6_2401-3del Likely benign ★★ same type
CAD c.6576-5del Benign ★★ same type
CAD c.2031+2_2031+12del Likely pathogenic ★ same type
CAD c.3618+1del Likely pathogenic ★ same type
CAD c.6320_6378+11del Likely pathogenic ★ same type
CAD p.Ala3_Leu4insTer Pathogenic ★ same type
CAD p.Ala519fs Pathogenic ★ 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-phe1766fs (accessed [today's date]).

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