Is CNPY2 p.Ala76Asp (c.227C>A) pathogenic?

CNPY2 p.Ala76Asp (c.227C>A) is classified Uncertain significance in CNPY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely pathogenic (0.9083); Absent from gnomAD v4.1.

How common is CNPY2 p.Ala76Asp (c.227C>A) in the general population?

CNPY2 p.Ala76Asp (c.227C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNPY2 p.Ala76Asp (c.227C>A)?

AlphaMissense predicts likely pathogenic (score 0.9083) — an in-silico prediction, not a clinical call.

CNPY2 p.Ala76Asp

c.227C>A · VCV4655007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9083 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9083	likely pathogenic
REVEL	0.226	benign-leaning
SaProt	LLR -13.25	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,662 bp · p 0.2 · regional, not allelic
Overall
CADD	27.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNPY2
Protein: p.Ala76Asp
Coding: c.227C>A
MANE Select: NM_014255
Type: single nucleotide variant
Location: chr12:56311392 (GRCh38)
Gene constraint: LOEUF 1.039 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.95
Residue 76: 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.Arg107His Uncertain significance ★ ⚠ same type
CNPY2 p.Arg111Gln 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-ala76asp (accessed [today's date]).

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