Is CPA2 p.Ile172Val (c.514A>G) pathogenic?

CPA2 p.Ile172Val (c.514A>G) is classified Benign in CPA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-05-31). AlphaMissense: likely benign (0.0975); Common (popmax 6.02%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CPA2 p.Ile172Val (c.514A>G)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

CPA2 p.Ile172Val

Q: How common is CPA2 p.Ile172Val (c.514A>G) in the general population?

CPA2 p.Ile172Val (c.514A>G) is common (popmax 6.02%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.514A>G · rs61731658 · VCV792089

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.02%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -6.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 23 kb · p 0.61 · regional, not allelic
Overall
CADD	19.02	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 6.02% African / African-American · 4,516/75,048 alleles

Filtering AF 5.87% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.81%

Overall 0.317% 5,113/1,614,110 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.02%	17
Remaining individualsnot grpmax-eligible	0.437%	229
Admixed American	0.405%	247
Middle Eastern	0.099%	1,010
South Asian	0.0154%	6,506
European (non-Finnish)	0.00517%	19,344

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: CPA2
Protein: p.Ile172Val
Coding: c.514A>G
MANE Select: NM_001869
dbSNP: rs61731658
Type: single nucleotide variant
Location: chr7:130275176 (GRCh38)
Gene constraint: LOEUF 1.282 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.00 · 3 PDB
Residue 172: the peptidase m14 domain; a β-strand

Full CPA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPA2 p.Ile172Thr Uncertain significance ★ ⚠ same residue
CPA2 p.Val67Ile Benign ★★ same type
CPA2 p.Ala122Asp Uncertain significance ★ ⚠ same type
CPA2 p.Ala176Val Uncertain significance ★ ⚠ same type
CPA2 p.Ala336Pro Uncertain significance ★ ⚠ same type
CPA2 p.Arg114Gln Uncertain significance ★ ⚠ same type
CPA2 p.Arg181Gln Uncertain significance ★ ⚠ same type
CPA2 p.Arg234His 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/cpa2-p-ile172val (accessed [today's date]).

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