Is CNP p.Ala269Val (c.806C>T) pathogenic?

CNP p.Ala269Val (c.806C>T) is classified Uncertain significance in CNP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely benign (0.1732); Very rare (popmax 0.00576%, nfe).

How common is CNP p.Ala269Val (c.806C>T) in the general population?

CNP p.Ala269Val (c.806C>T) is very rare (popmax 0.00576%, nfe) (gnomAD).

What do computational predictors say about CNP p.Ala269Val (c.806C>T)?

AlphaMissense predicts likely benign (score 0.1732) — an in-silico prediction, not a clinical call.

CNP p.Ala269Val

c.806C>T · VCV4654996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1732 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00576%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1732	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -6.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.51, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,251 bp · p 0.97 · regional, not allelic
Overall
CADD	21.2	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 0.00576% European (non-Finnish) · 68/1,179,814 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.00452% 73/1,613,576 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00576%	17,350
Remaining individualsnot grpmax-eligible	0.0048%	20,824
African / African-American	0.00134%	74,802
South Asian	0.0011%	91,066

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: CNP
Protein: p.Ala269Val
Coding: c.806C>T
MANE Select: NM_033133
Type: single nucleotide variant
Location: chr17:41972021 (GRCh38)
Gene constraint: LOEUF 0.379 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.54 · 1 PDB
Residue 269: an α-helix

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

Similar variants

CNP p.Arg353Trp Uncertain significance ★★ ⚠ same type
CNP p.Gly365= Benign ★★ same type
CNP p.Ala218Val Uncertain significance ★ ⚠ same type
CNP p.Ala281Val Uncertain significance ★ ⚠ same type
CNP p.Ala92Thr Uncertain significance ★ ⚠ same type
CNP p.Arg114Gln Uncertain significance ★ ⚠ same type
CNP p.Arg128Gln Uncertain significance ★ ⚠ same type
CNP p.Arg203Cys 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/cnp-p-ala269val (accessed [today's date]).

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