Is CDON p.Lys557= (c.1671G>A) pathogenic?

CDON p.Lys557= (c.1671G>A) is classified Benign/Likely benign in CDON (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Low-frequency (popmax 2.61%, nfe); Associated with holoprosencephaly 11.

What condition is associated with CDON p.Lys557= (c.1671G>A)?

CDON p.Lys557= (c.1671G>A) is associated with holoprosencephaly 11 (ClinVar).

How common is CDON p.Lys557= (c.1671G>A) in the general population?

CDON p.Lys557= (c.1671G>A) is low-frequency (popmax 2.61%, nfe) (gnomAD).

CDON p.Lys557=

c.1671G>A · rs35884952 · VCV260783

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.61%, nfe)

Conditions

holoprosencephaly 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.036	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -1.1, phastCons 0.18
Overall
CADD	3.103	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.61% European (non-Finnish) · 30,822/1,179,966 alleles

Filtering AF 2.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.58%

Overall 2.24% 36,103/1,614,058 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.23%	31
Amishnot grpmax-eligible	3.19%	31
European (non-Finnish)grpmax	2.61%	38
Remaining individualsnot grpmax-eligible	1.97%	51
Ashkenazi Jewishnot grpmax-eligible	1.64%	61
Admixed American	0.951%	105
Middle Eastern	0.676%	148
South Asian	0.629%	159
African / African-American	0.375%	267

Finnish 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.Lys557=
Coding: c.1671G>A
MANE Select: NM_001378964
dbSNP: rs35884952
Type: single nucleotide variant
Location: chr11:126005939 (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-lys557 (accessed [today's date]).

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