Is CPA5 p.Ala423Val (c.1268C>T) pathogenic?

CPA5 p.Ala423Val (c.1268C>T) is classified Uncertain significance in CPA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely pathogenic (0.621); Very rare (popmax 0.00119%, nfe).

How common is CPA5 p.Ala423Val (c.1268C>T) in the general population?

CPA5 p.Ala423Val (c.1268C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about CPA5 p.Ala423Val (c.1268C>T)?

AlphaMissense predicts likely pathogenic (score 0.621) — an in-silico prediction, not a clinical call.

CPA5 p.Ala423Val

c.1268C>T · rs782212383 · VCV2531656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.621	likely pathogenic
REVEL	0.274	benign-leaning
SaProt	LLR -14.57	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 22 kb · p 0.045 · regional, not allelic
Overall
CADD	24.7	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 0.00119% European (non-Finnish) · 14/1,180,026 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000929% 15/1,613,932 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00119%	84,288
South Asian	0.0011%	91,078

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: CPA5
Protein: p.Ala423Val
Coding: c.1268C>T
MANE Select: NM_080385
dbSNP: rs782212383
Type: single nucleotide variant
Location: chr7:130368554 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.56
Residue 423: the peptidase m14 domain

Full CPA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPA5 p.Ala120Thr Uncertain significance ★ ⚠ same type
CPA5 p.Ala188Val Uncertain significance ★ ⚠ same type
CPA5 p.Ala229Val Uncertain significance ★ ⚠ same type
CPA5 p.Ala350Asp Uncertain significance ★ ⚠ same type
CPA5 p.Ala356Val Uncertain significance ★ ⚠ same type
CPA5 p.Ala393Asp Uncertain significance ★ ⚠ same type
CPA5 p.Ala393Thr Uncertain significance ★ ⚠ same type
CPA5 p.Arg10Cys 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/cpa5-p-ala423val (accessed [today's date]).

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