Is CDON p.Arg744Trp (c.2230C>T) pathogenic?

CDON p.Arg744Trp (c.2230C>T) is classified Uncertain significance in CDON (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-19). AlphaMissense: likely pathogenic (0.7528); Very rare (popmax 0.00223%, eas); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Arg744Trp (c.2230C>T)?

CDON p.Arg744Trp (c.2230C>T) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Arg744Trp (c.2230C>T) in the general population?

CDON p.Arg744Trp (c.2230C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDON p.Arg744Trp (c.2230C>T)?

AlphaMissense predicts likely pathogenic (score 0.7528) — an in-silico prediction, not a clinical call.

CDON p.Arg744Trp

c.2230C>T · rs953453508 · VCV1393777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.7528	likely pathogenic
REVEL	0.593	indeterminate
SaProt	LLR -11.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,852 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000496% 8/1,613,870 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,852
African / African-American	0.00133%	74,916
South Asian	0.0011%	91,070
European (non-Finnish)	0.000424%	235,985

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.Arg744Trp
Coding: c.2230C>T
MANE Select: NM_001378964
dbSNP: rs953453508
Type: single nucleotide variant
Location: chr11:125997339 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 744: the fibronectin type-iii 2 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.Arg744= Likely benign ★ same residue
CDON p.Arg744Gln Uncertain significance ★ ⚠ 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

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-arg744trp (accessed [today's date]).

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