Is CNP p.Ala281Val (c.842C>T) pathogenic?

CNP p.Ala281Val (c.842C>T) is classified Uncertain significance in CNP (ClinVar, Single submitter, 1 submitter). AlphaMissense: ambiguous (0.4604); Absent from gnomAD v4.1; Associated with leukodystrophy, hypomyelinating, 20.

What condition is associated with CNP p.Ala281Val (c.842C>T)?

CNP p.Ala281Val (c.842C>T) is associated with leukodystrophy, hypomyelinating, 20 (ClinVar).

How common is CNP p.Ala281Val (c.842C>T) in the general population?

CNP p.Ala281Val (c.842C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNP p.Ala281Val (c.842C>T)?

AlphaMissense predicts ambiguous (score 0.4604) — an in-silico prediction, not a clinical call.

CNP p.Ala281Val

c.842C>T · rs2544758483 · VCV1878567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4604 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

leukodystrophy, hypomyelinating, 20

Computational evidence

Protein change
AlphaMissense	0.4604	ambiguous
REVEL	0.053	moderately benign-leaning
SaProt	LLR -4.40	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,251 bp · p 0.97 · regional, not allelic
Overall
CADD	22.3	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

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: CNP
Protein: p.Ala281Val
Coding: c.842C>T
MANE Select: NM_033133
dbSNP: rs2544758483
Type: single nucleotide variant
Location: chr17:41973500 (GRCh38)
Gene constraint: LOEUF 0.379 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 87.54 · 1 PDB
Residue 281: a β-strand

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

Disease context

leukodystrophy, hypomyelinating, 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNP p.Ser82Leu Pathogenic ⚠ same condition
CNP p.Gln306His Uncertain significance ★ same condition
CNP p.Arg353Trp Uncertain significance ★★ ⚠ same type
CNP p.Gly365= Benign ★★ same type
CNP p.Ala218Val Uncertain significance ★ ⚠ same type
CNP p.Ala269Val Uncertain significance ★ ⚠ same type
CNP p.Ala92Thr Uncertain significance ★ ⚠ same type
CNP p.Arg114Gln 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-ala281val (accessed [today's date]).

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