Is CDON p.Ala686Val (c.2057C>T) pathogenic?

CDON p.Ala686Val (c.2057C>T) is classified Benign in CDON (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.121); Common (popmax 18.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with holoprosencephaly 11.

What condition is associated with CDON p.Ala686Val (c.2057C>T)?

CDON p.Ala686Val (c.2057C>T) is associated with holoprosencephaly 11 (ClinVar).

What do computational predictors say about CDON p.Ala686Val (c.2057C>T)?

AlphaMissense predicts likely benign (score 0.121) — an in-silico prediction, not a clinical call.

CDON p.Ala686Val

Q: How common is CDON p.Ala686Val (c.2057C>T) in the general population?

CDON p.Ala686Val (c.2057C>T) is common (popmax 18.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2057C>T · rs12274923 · VCV260785

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.121 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 18.9%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 11

Computational evidence

Protein change
AlphaMissense	0.121	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -6.11	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 -1.1, phastCons 0.97
Regional constraint	o/e 0.93	unconstrained · MANE · 63 kb · p 0.0032 · regional, not allelic
Overall
CADD	14.34	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 18.9% European (non-Finnish) · 220,079/1,162,492 alleles

Filtering AF 18.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 18.8%

Overall 17.8% 284,049/1,595,034 alleles · common exomes 259,760/1,442,894 · genomes 24,289/152,140 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	28.6%	3
Finnishnot grpmax-eligible	21.8%	5
Ashkenazi Jewishnot grpmax-eligible	21.6%	5
European (non-Finnish)grpmax	18.9%	5
Remaining individualsnot grpmax-eligible	16.8%	6
Admixed American	15.9%	6
South Asian	14%	7
Middle Eastern	13%	8
African / African-American	8.92%	11
East Asian	7.35%	14

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala686Val
Coding: c.2057C>T
MANE Select: NM_001378964
dbSNP: rs12274923
Type: single nucleotide variant
Location: chr11:126001820 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.62 · 3 PDB
Residue 686: a UniProt-annotated variant site (in)

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.Ala686Ser 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
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-ala686val (accessed [today's date]).

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