Is CDON p.Lys66Arg (c.197A>G) pathogenic?

CDON p.Lys66Arg (c.197A>G) is classified Benign in CDON (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-26). AlphaMissense: likely benign (0.104); Common (popmax 8.25%, afr) — too common for a highly-penetrant pathogenic allele; Associated with holoprosencephaly 11.

What condition is associated with CDON p.Lys66Arg (c.197A>G)?

CDON p.Lys66Arg (c.197A>G) is associated with holoprosencephaly 11 (ClinVar).

What do computational predictors say about CDON p.Lys66Arg (c.197A>G)?

AlphaMissense predicts likely benign (score 0.104) — an in-silico prediction, not a clinical call.

CDON p.Lys66Arg

Q: How common is CDON p.Lys66Arg (c.197A>G) in the general population?

CDON p.Lys66Arg (c.197A>G) is common (popmax 8.25%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.197A>G · rs7122277 · VCV303523

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.104 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.25%, 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	0.104	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.71	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 1.9	GERP -2.5, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	10.79	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 8.25% African / African-American · 6,184/74,988 alleles

Filtering AF 8.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 8%

Overall 0.449% 7,252/1,614,090 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	8.25%	12
Admixed American	0.595%	168
Remaining individualsnot grpmax-eligible	0.528%	189
Middle Eastern	0.28%	357
European (non-Finnish)	0.0292%	3,420
South Asian	0.0198%	5,060
Finnishnot grpmax-eligible	0.00156%	64,036

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.Lys66Arg
Coding: c.197A>G
MANE Select: NM_001378964
dbSNP: rs7122277
Type: single nucleotide variant
Location: chr11:126021400 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 66: a disulfide bond; a UniProt-annotated variant site (in); 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 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
CDON p.Ala1099Val 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-lys66arg (accessed [today's date]).

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