Is CDON p.Val299Ala (c.896T>C) pathogenic?

CDON p.Val299Ala (c.896T>C) is classified Uncertain significance in CDON (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: ambiguous (0.4313); Very rare (popmax 0.000339%, nfe); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Val299Ala (c.896T>C)?

CDON p.Val299Ala (c.896T>C) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Val299Ala (c.896T>C) in the general population?

CDON p.Val299Ala (c.896T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CDON p.Val299Ala (c.896T>C)?

AlphaMissense predicts ambiguous (score 0.4313) — an in-silico prediction, not a clinical call.

CDON p.Val299Ala

c.896T>C · rs980315790 · VCV2852822

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4313 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.4313	ambiguous
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.88	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 3.2	GERP -2.1, phastCons 0.013
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	10.83	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 0.000339% European (non-Finnish) · 4/1,179,984 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,032 alleles · very rare

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: CDON
Protein: p.Val299Ala
Coding: c.896T>C
MANE Select: NM_001378964
dbSNP: rs980315790
Type: single nucleotide variant
Location: chr11:126017120 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 299: the ig-like c2-type 3 domain

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

Disease context

holoprosencephaly 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDON p.Val299= Likely benign ★ same residue
CDON c.3276+1G>T Uncertain significance ★★ same condition
CDON c.640+1G>A Uncertain significance ★★ same condition
CDON c.*1805A>G Uncertain significance ★★ same condition
CDON c.*1816C>T Uncertain significance ★★ same condition
CDON c.*2349A>C Uncertain significance ★★ same condition
CDON c.*2377T>C Uncertain significance ★★ same condition
CDON c.*2760A>G Uncertain significance ★★ same condition

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/cdon-p-val299ala (accessed [today's date]).

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