Is CNPY2 p.Arg111Gln (c.332G>A) pathogenic?

CNPY2 p.Arg111Gln (c.332G>A) is classified Uncertain significance in CNPY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely benign (0.2362); Ultra-rare (popmax 0.015%, amr).

How common is CNPY2 p.Arg111Gln (c.332G>A) in the general population?

CNPY2 p.Arg111Gln (c.332G>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about CNPY2 p.Arg111Gln (c.332G>A)?

AlphaMissense predicts likely benign (score 0.2362) — an in-silico prediction, not a clinical call.

CNPY2 p.Arg111Gln

c.332G>A · VCV4230990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2362 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2362	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -7.92	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 6	GERP 0.52, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,662 bp · p 0.2 · regional, not allelic
Overall
CADD	28.6	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 0.015% Admixed American · 9/59,990 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00242% 39/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,666
European (non-Finnish)	0.00237%	42,144
Finnishnot grpmax-eligible	0.00156%	64,030
South Asian	0.0011%	91,070

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: CNPY2
Protein: p.Arg111Gln
Coding: c.332G>A
MANE Select: NM_014255
Type: single nucleotide variant
Location: chr12:56311287 (GRCh38)
Gene constraint: LOEUF 1.039 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.95
Residue 111: the saposin b-type domain; a disulfide bond

Full CNPY2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNPY2 p.Ala156Val Uncertain significance ★ ⚠ same type
CNPY2 p.Ala174Thr Uncertain significance ★ ⚠ same type
CNPY2 p.Ala18Ser Uncertain significance ★ ⚠ same type
CNPY2 p.Ala76Asp Uncertain significance ★ ⚠ same type
CNPY2 p.Arg107His Uncertain significance ★ ⚠ same type
CNPY2 p.Arg124Gln Uncertain significance ★ ⚠ same type
CNPY2 p.Arg154Gln Uncertain significance ★ ⚠ same type
CNPY2 p.Arg21Trp 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/cnpy2-p-arg111gln (accessed [today's date]).

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