Is CAD p.Asp1808His (c.5422G>C) pathogenic?

CAD p.Asp1808His (c.5422G>C) is classified Uncertain significance in CAD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-01). AlphaMissense: likely pathogenic (0.9151); Very rare (popmax 0.00113%, sas).

How common is CAD p.Asp1808His (c.5422G>C) in the general population?

CAD p.Asp1808His (c.5422G>C) is very rare (popmax 0.00113%, sas) (gnomAD).

What do computational predictors say about CAD p.Asp1808His (c.5422G>C)?

AlphaMissense predicts likely pathogenic (score 0.9151) — an in-silico prediction, not a clinical call.

CAD p.Asp1808His

c.5422G>C · rs1378731205 · VCV2122756

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9151 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9151	likely pathogenic
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -10.11	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, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 2,919 bp · p 0.1 · regional, not allelic
Overall
CADD	28.4	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 0.00113% South Asian · 1/88,322 alleles

Overall 6.93e-05% 1/1,442,312 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.Asp1808His
Coding: c.5422G>C
MANE Select: NM_004341
dbSNP: rs1378731205
Type: single nucleotide variant
Location: chr2:27239724 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 1808: a UniProt-annotated variant site (in dee50; uncertain significance); the 'linker' region

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

Similar variants

CAD p.Asp1808fs Pathogenic ★ 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-asp1808his (accessed [today's date]).

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