Is CPZ p.Ala262Val (c.785C>T) pathogenic?

CPZ p.Ala262Val (c.785C>T) is classified Uncertain significance in CPZ (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: ambiguous (0.4619); Very rare (popmax 0.004%, afr).

How common is CPZ p.Ala262Val (c.785C>T) in the general population?

CPZ p.Ala262Val (c.785C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CPZ p.Ala262Val (c.785C>T)?

AlphaMissense predicts ambiguous (score 0.4619) — an in-silico prediction, not a clinical call.

CPZ p.Ala262Val

c.785C>T · VCV4006501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4619	ambiguous
REVEL	0.16	moderately benign-leaning
SaProt	LLR -9.36	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -4.2, phastCons 1
Regional constraint	o/e 1.60	unconstrained · MANE · 27 kb · p 7.4e-73 · regional, not allelic
Overall
CADD	25.3	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 0.004% African / African-American · 3/74,926 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000434% 7/1,614,080 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
European (non-Finnish)	0.000339%	295,010

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.Ala262Val
Coding: c.785C>T
MANE Select: NM_001014447
Type: single nucleotide variant
Location: chr4:8606064 (GRCh38)
Gene constraint: LOEUF 1.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.33
Residue 262: the peptidase m14 domain

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

Similar variants

CPZ p.Ala262Thr Uncertain significance ★ ⚠ same residue
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

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-ala262val (accessed [today's date]).

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