Is CNPY3 p.Pro258= (c.774C>T) pathogenic?

CNPY3 p.Pro258= (c.774C>T) is classified Likely benign in CNPY3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-01-04). Very rare (popmax 0.00517%, nfe); Associated with CNPY3-related disorder.

What condition is associated with CNPY3 p.Pro258= (c.774C>T)?

CNPY3 p.Pro258= (c.774C>T) is associated with CNPY3-related disorder (ClinVar).

How common is CNPY3 p.Pro258= (c.774C>T) in the general population?

CNPY3 p.Pro258= (c.774C>T) is very rare (popmax 0.00517%, nfe) (gnomAD).

CNPY3 p.Pro258=

c.774C>T · rs1256509421 · VCV3032401

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Conditions

CNPY3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3
Overall
CADD	1.373	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00517% European (non-Finnish) · 61/1,179,894 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00409% 66/1,613,742 alleles · very rare exomes 63/1,461,646 · genomes 3/152,096 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,343
African / African-American	0.00267%	37,449
East Asian	0.00223%	44,890
Remaining individualsnot grpmax-eligible	0.0016%	62,476
South Asian	0.0011%	91,052

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: CNPY3
Protein: p.Pro258=
Coding: c.774C>T
MANE Select: NM_006586
dbSNP: rs1256509421
Type: single nucleotide variant
Location: chr6:42938728 (GRCh38)
Gene constraint: LOEUF 0.882 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.76
Residue 258: the saposin b-type domain; the 'disordered' region

Full CNPY3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CNPY3-related disorder

Similar variants

CNPY3 p.Arg106Met Uncertain significance ⚠ same condition
CNPY3 p.Ser92Leu Uncertain significance ⚠ same condition
CNPY3 p.Ala220Thr Likely benign same condition
CNPY3 p.Leu25_Pro26insLeu Likely benign same condition
CNPY3 p.Leu25del Benign same condition
CNPY3 p.Glu154Lys Uncertain significance ★★ ⚠ same type
CNPY3 p.Glu98Lys Uncertain significance ★★ ⚠ same type
CNPY3 p.Gly67Ser 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/cnpy3-p-pro258 (accessed [today's date]).

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