Is CDON p.Arg992Cys (c.2974C>T) pathogenic?

CDON p.Arg992Cys (c.2974C>T) is classified Uncertain significance in CDON (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). AlphaMissense: likely pathogenic (0.6619); Ultra-rare (popmax 0.0223%, eas); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Arg992Cys (c.2974C>T)?

CDON p.Arg992Cys (c.2974C>T) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Arg992Cys (c.2974C>T) in the general population?

CDON p.Arg992Cys (c.2974C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about CDON p.Arg992Cys (c.2974C>T)?

AlphaMissense predicts likely pathogenic (score 0.6619) — an in-silico prediction, not a clinical call.

CDON p.Arg992Cys

c.2974C>T · VCV3664587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6619 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.6619	likely pathogenic
REVEL	0.238	benign-leaning
SaProt	LLR -8.01	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP -0.64, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	26.1	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 0.0223% East Asian · 10/44,870 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.00136% 22/1,613,630 alleles · ultra-rare exomes 21/1,461,400 · genomes 1/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,487
Admixed American	0.0117%	8,574
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000339%	294,918

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.Arg992Cys
Coding: c.2974C>T
MANE Select: NM_001378964
Type: single nucleotide variant
Location: chr11:125983893 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB

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-arg992cys (accessed [today's date]).

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