Is CPA5 p.Pro261Leu (c.782C>T) pathogenic?

CPA5 p.Pro261Leu (c.782C>T) is classified Uncertain significance in CPA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.1431); Ultra-rare (popmax 0.0129%, amr).

How common is CPA5 p.Pro261Leu (c.782C>T) in the general population?

CPA5 p.Pro261Leu (c.782C>T) is ultra-rare (popmax 0.0129%, amr) (gnomAD).

What do computational predictors say about CPA5 p.Pro261Leu (c.782C>T)?

AlphaMissense predicts likely benign (score 0.1431) — an in-silico prediction, not a clinical call.

CPA5 p.Pro261Leu

c.782C>T · VCV4656012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1431 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1431	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -10.45	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.53, phastCons 0.62
Regional constraint	o/e 0.92	unconstrained · MANE · 22 kb · p 0.045 · regional, not allelic
Overall
CADD	21.4	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 0.0129% Admixed American · 7/54,292 alleles

Filtering AF 0.00604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.000569% 9/1,581,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0129%	7,756
Remaining individualsnot grpmax-eligible	0.00163%	61,438
European (non-Finnish)	8.59e-05%	1,163,569

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.Pro261Leu
Coding: c.782C>T
MANE Select: NM_080385
Type: single nucleotide variant
Location: chr7:130363453 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.56
Residue 261: 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.Ala423Val 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-pro261leu (accessed [today's date]).

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