Is CDON p.Val75Ile (c.223G>A) pathogenic?

CDON p.Val75Ile (c.223G>A) is classified Benign in CDON (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.1182); Common (popmax 81.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with holoprosencephaly 11.

What condition is associated with CDON p.Val75Ile (c.223G>A)?

CDON p.Val75Ile (c.223G>A) is associated with holoprosencephaly 11 (ClinVar).

What do computational predictors say about CDON p.Val75Ile (c.223G>A)?

AlphaMissense predicts likely benign (score 0.1182) — an in-silico prediction, not a clinical call.

CDON p.Val75Ile

Q: How common is CDON p.Val75Ile (c.223G>A) in the general population?

CDON p.Val75Ile (c.223G>A) is common (popmax 81.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.223G>A · rs3740912 · VCV95752

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1182 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 81.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.1182	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -2.6, phastCons 0.96
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	6.684	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 81.9% African / African-American · 61,405/74,948 alleles

Filtering AF 81.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.2%

Overall 56.4% 910,742/1,613,614 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	81.9%	1
Amishnot grpmax-eligible	70.8%	1
Finnishnot grpmax-eligible	63.1%	2
Ashkenazi Jewishnot grpmax-eligible	60.4%	2
Remaining individualsnot grpmax-eligible	56.9%	2
European (non-Finnish)	55.8%	2
Middle Eastern	55.2%	2
South Asian	52.7%	2
Admixed American	52.2%	2
East Asian	30.5%	3

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.Val75Ile
Coding: c.223G>A
MANE Select: NM_001378964
dbSNP: rs3740912
Type: single nucleotide variant
Location: chr11:126021374 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 75: a disulfide bond; the ig-like c2-type 1 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.Val75= 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-val75ile (accessed [today's date]).

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