Is CNPY2 p.Arg107His (c.320G>A) pathogenic?

CNPY2 p.Arg107His (c.320G>A) is classified Uncertain significance in CNPY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). AlphaMissense: likely pathogenic (0.6481); Very rare (popmax 0.00223%, eas).

How common is CNPY2 p.Arg107His (c.320G>A) in the general population?

CNPY2 p.Arg107His (c.320G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CNPY2 p.Arg107His (c.320G>A)?

AlphaMissense predicts likely pathogenic (score 0.6481) — an in-silico prediction, not a clinical call.

CNPY2 p.Arg107His

c.320G>A · rs766973735 · VCV3146652

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6481	likely pathogenic
REVEL	0.25	benign-leaning
SaProt	LLR -9.55	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 4,662 bp · p 0.2 · regional, not allelic
Overall
CADD	25.8	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 0.00223% East Asian · 1/44,892 alleles

Overall 0.00223% 36/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0484%	2,065
East Asiangrpmax	0.00223%	44,892
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,482
South Asian	0.0011%	91,082
European (non-Finnish)	8.47e-05%	1,180,032

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg107His
Coding: c.320G>A
MANE Select: NM_014255
dbSNP: rs766973735
Type: single nucleotide variant
Location: chr12:56311299 (GRCh38)
Gene constraint: LOEUF 1.039 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.95
Residue 107: 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.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-arg107his (accessed [today's date]).

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