Is CPA5 p.Arg44Gln (c.131G>A) pathogenic?

CPA5 p.Arg44Gln (c.131G>A) is classified Uncertain significance in CPA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely benign (0.1792); Ultra-rare (popmax 0.0214%, nfe).

How common is CPA5 p.Arg44Gln (c.131G>A) in the general population?

CPA5 p.Arg44Gln (c.131G>A) is ultra-rare (popmax 0.0214%, nfe) (gnomAD).

What do computational predictors say about CPA5 p.Arg44Gln (c.131G>A)?

AlphaMissense predicts likely benign (score 0.1792) — an in-silico prediction, not a clinical call.

CPA5 p.Arg44Gln

c.131G>A · rs138657131 · VCV2370643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1792	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -8.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 22 kb · p 0.045 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0214% European (non-Finnish) · 253/1,179,926 alleles

Filtering AF 0.0193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0164% 264/1,613,682 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0214%	4,664
Remaining individualsnot grpmax-eligible	0.0064%	15,620
African / African-American	0.00535%	18,707
East Asian	0.00223%	44,862
South Asian	0.0022%	45,516

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.Arg44Gln
Coding: c.131G>A
MANE Select: NM_080385
dbSNP: rs138657131
Type: single nucleotide variant
Location: chr7:130347780 (GRCh38)
Gene constraint: LOEUF 1.11 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.56

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-arg44gln (accessed [today's date]).

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