Is CAD p.Pro391fs (c.1172del) pathogenic?

CAD p.Pro391fs (c.1172del) is classified Pathogenic in CAD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-23). Very rare (popmax 0.000169%, nfe).

How common is CAD p.Pro391fs (c.1172del) in the general population?

CAD p.Pro391fs (c.1172del) is very rare (popmax 0.000169%, nfe) (gnomAD).

CAD p.Pro391fs

c.1172del · rs2148063184 · VCV1446574

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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 9 of 44
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.14	GERP -3.6, phastCons 0.61

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,026 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,894 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.Pro391fs
Coding: c.1172del
MANE Select: NM_004341
dbSNP: rs2148063184
Type: Deletion
Location: chr2:27224407 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 391: the 'linker' region

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

Similar variants

CAD p.Pro391Arg Uncertain significance ★ ⚠ same residue
CAD p.Pro391= Likely benign ★ same residue
CAD p.Gly725fs Pathogenic/Likely pathogenic ★★ same type
CAD p.Phe1766fs 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

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-pro391fs (accessed [today's date]).

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