Is CPA3 p.Arg273Pro (c.818G>C) pathogenic?

CPA3 p.Arg273Pro (c.818G>C) is classified Benign in CPA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-16). AlphaMissense: likely benign (0.2173); Low-frequency (popmax 1.03%, nfe).

How common is CPA3 p.Arg273Pro (c.818G>C) in the general population?

CPA3 p.Arg273Pro (c.818G>C) is low-frequency (popmax 1.03%, nfe) (gnomAD).

What do computational predictors say about CPA3 p.Arg273Pro (c.818G>C)?

AlphaMissense predicts likely benign (score 0.2173) — an in-silico prediction, not a clinical call.

CPA3 p.Arg273Pro

c.818G>C · rs143184657 · VCV708072

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2173 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.03%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2173	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -4.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.24	GERP 0.072
Overall
CADD	18.56	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 1.03% European (non-Finnish) · 12,173/1,179,950 alleles

Filtering AF 1.02% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.01%

Overall 0.872% 14,067/1,613,932 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.86%	54
European (non-Finnish)grpmax	1.03%	97
Remaining individualsnot grpmax-eligible	0.896%	112
Admixed American	0.868%	115
Ashkenazi Jewishnot grpmax-eligible	0.78%	128
Finnishnot grpmax-eligible	0.297%	337
South Asian	0.28%	357
Middle Eastern	0.198%	505
African / African-American	0.144%	694

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CPA3
Protein: p.Arg273Pro
Coding: c.818G>C
MANE Select: NM_016352 · reported on NM_001870
dbSNP: rs143184657
Type: single nucleotide variant
Location: chr3:148883652 (GRCh38)
Structure: AlphaFold pLDDT 93.88 · 5 PDB
Residue 273: a disulfide bond; the peptidase m14 domain

Full CPA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPA3 p.Arg273Gln Uncertain significance ★ ⚠ same residue
CPA3 p.Thr283Met Benign ★★ ⚠ same type
CPA3 p.Ala117Thr Uncertain significance ★ ⚠ same type
CPA3 p.Ala15Thr Uncertain significance ★ ⚠ same type
CPA3 p.Ala177Thr Uncertain significance ★ ⚠ same type
CPA3 p.Ala56Thr Uncertain significance ★ ⚠ same type
CPA3 p.Ala77Thr Uncertain significance ★ ⚠ same type
CPA3 p.Arg20His 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/cpa3-p-arg273pro (accessed [today's date]).

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