Is CPA5 p.Ser299Leu (c.896C>T) pathogenic?

CPA5 p.Ser299Leu (c.896C>T) is classified Uncertain significance in CPA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-22). AlphaMissense: ambiguous (0.553); Ultra-rare (popmax 0.045%, nfe).

How common is CPA5 p.Ser299Leu (c.896C>T) in the general population?

CPA5 p.Ser299Leu (c.896C>T) is ultra-rare (popmax 0.045%, nfe) (gnomAD).

What do computational predictors say about CPA5 p.Ser299Leu (c.896C>T)?

AlphaMissense predicts ambiguous (score 0.553) — an in-silico prediction, not a clinical call.

CPA5 p.Ser299Leu

c.896C>T · rs142001870 · VCV2341197

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.553 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, nfe)

Computational evidence

Protein change
AlphaMissense	0.553	ambiguous
REVEL	0.303	indeterminate
SaProt	LLR -10.63	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 22 kb · p 0.045 · regional, not allelic
Overall
CADD	31.0	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 0.045% European (non-Finnish) · 531/1,180,030 alleles

Filtering AF 0.0418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0405%

Overall 0.0357% 576/1,614,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.045%	2,222
Remaining individualsnot grpmax-eligible	0.0192%	5,209
Finnishnot grpmax-eligible	0.0187%	5,335
Middle Eastern	0.0165%	6,054
South Asian	0.00988%	10,118
African / African-American	0.00933%	10,719
Admixed American	0.005%	20,005
East Asian	0.00223%	44,882

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.Ser299Leu
Coding: c.896C>T
MANE Select: NM_080385
dbSNP: rs142001870
Type: single nucleotide variant
Location: chr7:130367429 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.56
Residue 299: 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-ser299leu (accessed [today's date]).

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