Is CAD p.Pro1702Ser (c.5104C>T) pathogenic?

CAD p.Pro1702Ser (c.5104C>T) is classified Uncertain significance in CAD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-24). AlphaMissense: ambiguous (0.4902); Rare (popmax 0.1%, sas); Associated with developmental and epileptic encephalopathy, 50.

What condition is associated with CAD p.Pro1702Ser (c.5104C>T)?

CAD p.Pro1702Ser (c.5104C>T) is associated with developmental and epileptic encephalopathy, 50 (ClinVar).

How common is CAD p.Pro1702Ser (c.5104C>T) in the general population?

CAD p.Pro1702Ser (c.5104C>T) is rare (popmax 0.1%, sas) (gnomAD).

How is CAD-CDG inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CAD p.Pro1702Ser (c.5104C>T)?

AlphaMissense predicts ambiguous (score 0.4902) — an in-silico prediction, not a clinical call.

CAD p.Pro1702Ser

c.5104C>T · rs529298259 · VCV1699465

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4902 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.1%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

developmental and epileptic encephalopathy, 50

Computational evidence

Protein change
AlphaMissense	0.4902	ambiguous
REVEL	0.729	pathogenic-leaning
SaProt	LLR -6.36	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 2,919 bp · p 0.1 · regional, not allelic
Overall
CADD	24.9	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 0.1% South Asian · 89/88,656 alleles

Filtering AF 0.0835% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0772%

Overall 0.00582% 93/1,598,794 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.1%	996
Remaining individualsnot grpmax-eligible	0.00486%	20,595
European (non-Finnish)	8.52e-05%	1,173,184

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.Pro1702Ser
Coding: c.5104C>T
MANE Select: NM_004341
dbSNP: rs529298259
Type: single nucleotide variant
Location: chr2:27239083 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 1702: the 'dhoase (dihydroorotase)' region; an α-helix; a binding site

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

Disease context

developmental and epileptic encephalopathy, 50 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CAD-CDG (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CAD p.Arg1789Ter Pathogenic ★★ same condition
CAD p.Arg1810Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
CAD p.Arg191Ter Pathogenic ★★ same condition
CAD p.Gln1604Ter Likely pathogenic ★★ same condition
CAD p.Met33Arg Pathogenic ★★ same condition
CAD c.4315-3C>T Uncertain significance ★★ same condition
CAD c.996-13A>G Uncertain significance ★★ same condition
CAD c.996-4A>G Uncertain significance ★★ same condition

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-pro1702ser (accessed [today's date]).

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