Is CNTN2 p.Ser407= (c.1221C>T) pathogenic?

CNTN2 p.Ser407= (c.1221C>T) is classified Likely benign in CNTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). Ultra-rare (popmax 0.0164%, mid); Associated with epilepsy, familial adult myoclonic, 5.

What condition is associated with CNTN2 p.Ser407= (c.1221C>T)?

CNTN2 p.Ser407= (c.1221C>T) is associated with epilepsy, familial adult myoclonic, 5 (ClinVar).

How common is CNTN2 p.Ser407= (c.1221C>T) in the general population?

CNTN2 p.Ser407= (c.1221C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

CNTN2 p.Ser407=

c.1221C>T · rs774139246 · VCV725946

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

epilepsy, familial adult myoclonic, 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7	GERP -4.6
Overall
CADD	3.073	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00285% 46/1,613,318 alleles · ultra-rare exomes 40/1,461,102 · genomes 6/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
East Asian	0.0134%	7,477
Admixed American	0.00501%	19,963
Remaining individualsnot grpmax-eligible	0.0048%	20,820
South Asian	0.0044%	22,752
European (non-Finnish)	0.00237%	42,130
Finnishnot grpmax-eligible	0.00156%	63,974

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: CNTN2
Protein: p.Ser407=
Coding: c.1221C>T
MANE Select: NM_005076
dbSNP: rs774139246
Type: single nucleotide variant
Location: chr1:205062550 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 86.13 · 5 PDB
Residue 407: the ig-like c2-type 4 domain; a β-strand

Full CNTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy, familial adult myoclonic, 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNTN2 c.1241-1G>C Likely pathogenic ★★ same condition
CNTN2 c.2432-2A>G Likely pathogenic ★★ same condition
CNTN2 p.Arg140Ter Pathogenic/Likely pathogenic ★★ same condition
CNTN2 p.Arg314Ter Pathogenic ★★ same condition
CNTN2 p.Trp731Ter Pathogenic/Likely pathogenic ★★ same condition
CNTN2 c.2196+5G>A Uncertain significance ★★ same condition
CNTN2 p.Ala230Val Uncertain significance ★★ ⚠ same condition
CNTN2 p.Ala263Thr 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/cntn2-p-ser407 (accessed [today's date]).

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