Is CAD p.Ala727Ser (c.2179G>T) pathogenic?

CAD p.Ala727Ser (c.2179G>T) is classified Uncertain significance in CAD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-22). AlphaMissense: likely benign (0.1472); Very rare (popmax 0.0022%, sas).

How common is CAD p.Ala727Ser (c.2179G>T) in the general population?

CAD p.Ala727Ser (c.2179G>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CAD p.Ala727Ser (c.2179G>T)?

AlphaMissense predicts likely benign (score 0.1472) — an in-silico prediction, not a clinical call.

CAD p.Ala727Ser

c.2179G>T · rs770968496 · VCV1346174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1472	likely benign
REVEL	0.52	indeterminate
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -5.2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 7,481 bp · p 8.7e-11 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0022% South Asian · 2/91,082 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000342% 5/1,461,856 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,541
European (non-Finnish)	0.000254%	393,337

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.Ala727Ser
Coding: c.2179G>T
MANE Select: NM_004341
dbSNP: rs770968496
Type: single nucleotide variant
Location: chr2:27226854 (GRCh38)
Gene constraint: LOEUF 0.409 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.25 · 57 PDB
Residue 727: the 'cpsase (carbamoyl phosphate synthase)' region; the 'cpsase a' region

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

Similar variants

CAD p.Ala727Val 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-ala727ser (accessed [today's date]).

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