Is CNTN2 p.Pro989= (c.2967C>T) pathogenic?

CNTN2 p.Pro989= (c.2967C>T) is classified Likely benign in CNTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). Ultra-rare (popmax 0.0178%, eas); Associated with epilepsy, familial adult myoclonic, 5.

What condition is associated with CNTN2 p.Pro989= (c.2967C>T)?

CNTN2 p.Pro989= (c.2967C>T) is associated with epilepsy, familial adult myoclonic, 5 (ClinVar).

How common is CNTN2 p.Pro989= (c.2967C>T) in the general population?

CNTN2 p.Pro989= (c.2967C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

CNTN2 p.Pro989=

c.2967C>T · rs766320758 · VCV2887115

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

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	<0.2	all four deltas below 0.2 · C>G here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.7	GERP -4
Overall
CADD	7.432	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,900 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00136% 22/1,613,924 alleles · ultra-rare exomes 21/1,461,844 · genomes 1/152,080 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,612
Middle Eastern	0.0164%	6,082
South Asian	0.00329%	30,360
African / African-American	0.00267%	37,437
Admixed American	0.00167%	59,998
European (non-Finnish)	0.000593%	168,569

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.Pro989=
Coding: c.2967C>T
MANE Select: NM_005076
dbSNP: rs766320758
Type: single nucleotide variant
Location: chr1:205073190 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 86.13 · 5 PDB
Residue 989: the fibronectin type-iii 4 domain

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 p.Pro989Leu Uncertain significance ★ ⚠ same residue
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

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-pro989 (accessed [today's date]).

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