Is CPZ p.Ala299Val (c.896C>T) pathogenic?

CPZ p.Ala299Val (c.896C>T) is classified Uncertain significance in CPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely pathogenic (0.8934); Very rare (popmax 0.00805%, nfe).

How common is CPZ p.Ala299Val (c.896C>T) in the general population?

CPZ p.Ala299Val (c.896C>T) is very rare (popmax 0.00805%, nfe) (gnomAD).

What do computational predictors say about CPZ p.Ala299Val (c.896C>T)?

AlphaMissense predicts likely pathogenic (score 0.8934) — an in-silico prediction, not a clinical call.

CPZ p.Ala299Val

c.896C>T · VCV3496732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00805%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8934	likely pathogenic
REVEL	0.287	benign-leaning
SaProt	LLR -9.87	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.55 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.60	unconstrained · MANE · 27 kb · p 7.4e-73 · regional, not allelic
Overall
CADD	25.1	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 0.00805% European (non-Finnish) · 95/1,179,836 alleles

Filtering AF 0.00672% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00625%

Overall 0.00607% 98/1,613,522 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00805%	12,419
African / African-American	0.00267%	37,468
Remaining individualsnot grpmax-eligible	0.0016%	62,458

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: CPZ
Protein: p.Ala299Val
Coding: c.896C>T
MANE Select: NM_001014447
Type: single nucleotide variant
Location: chr4:8606175 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.33
Residue 299: the peptidase m14 domain

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

Similar variants

CPZ p.Gln317Ter Uncertain significance ★★ same type
CPZ c.1068+9C>T Benign ★★ same type
CPZ c.1604-8G>T Benign ★★ same type
CPZ p.Arg522= Benign ★★ same type
CPZ p.Arg647= Likely benign ★★ same type
CPZ p.Asn250= Benign ★★ same type
CPZ p.Gln263Arg Benign ★★ ⚠ same type
CPZ p.Pro618= Benign ★★ 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/cpz-p-ala299val (accessed [today's date]).

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