Is CNPY2 p.Trp40Ser (c.119G>C) pathogenic?

CNPY2 p.Trp40Ser (c.119G>C) is classified Uncertain significance in CNPY2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.7573); Ultra-rare (popmax 0.0267%, eas).

How common is CNPY2 p.Trp40Ser (c.119G>C) in the general population?

CNPY2 p.Trp40Ser (c.119G>C) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about CNPY2 p.Trp40Ser (c.119G>C)?

AlphaMissense predicts likely pathogenic (score 0.7573) — an in-silico prediction, not a clinical call.

CNPY2 p.Trp40Ser

c.119G>C · VCV4230994

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7573 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7573	likely pathogenic
REVEL	0.461	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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	29.3	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 0.0267% East Asian · 12/44,876 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.000805% 13/1,614,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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.Trp40Ser
Coding: c.119G>C
MANE Select: NM_014255
Type: single nucleotide variant
Location: chr12:56314936 (GRCh38)
Gene constraint: LOEUF 1.039 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.95
Residue 40: 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.Arg111Gln Uncertain significance ★ ⚠ same type
CNPY2 p.Arg124Gln Uncertain significance ★ ⚠ same type
CNPY2 p.Arg154Gln 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-trp40ser (accessed [today's date]).

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