Is CPA5 p.Arg129His (c.386G>A) pathogenic?

CPA5 p.Arg129His (c.386G>A) is classified Uncertain significance in CPA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-07). AlphaMissense: likely benign (0.124); Ultra-rare (popmax 0.0332%, mid).

How common is CPA5 p.Arg129His (c.386G>A) in the general population?

CPA5 p.Arg129His (c.386G>A) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about CPA5 p.Arg129His (c.386G>A)?

AlphaMissense predicts likely benign (score 0.124) — an in-silico prediction, not a clinical call.

CPA5 p.Arg129His

c.386G>A · rs200500417 · VCV2509491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.124 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.124	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -10.68	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 10	GERP 2.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 22 kb · p 0.045 · regional, not allelic
Overall
CADD	27.1	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 0.0332% Middle Eastern · 2/6,026 alleles

Filtering AF 0.0143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0122%

Overall 0.0138% 219/1,584,950 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,013
South Asian	0.022%	4,540
Remaining individualsnot grpmax-eligible	0.0195%	5,123
European (non-Finnish)	0.0147%	6,816
Admixed American	0.0127%	7,888
East Asian	0.0114%	8,778
African / African-American	0.00268%	37,383
Finnishnot grpmax-eligible	0.00162%	61,848

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.Arg129His
Coding: c.386G>A
MANE Select: NM_080385
dbSNP: rs200500417
Type: single nucleotide variant
Location: chr7:130359641 (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-arg129his (accessed [today's date]).

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