Is CNTN2 p.Ser86Pro (c.256T>C) pathogenic?

CNTN2 p.Ser86Pro (c.256T>C) is classified Uncertain significance in CNTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.6246); Very rare (popmax 0.00136%, afr); Associated with epilepsy, familial adult myoclonic, 5.

What condition is associated with CNTN2 p.Ser86Pro (c.256T>C)?

CNTN2 p.Ser86Pro (c.256T>C) is associated with epilepsy, familial adult myoclonic, 5 (ClinVar).

How common is CNTN2 p.Ser86Pro (c.256T>C) in the general population?

CNTN2 p.Ser86Pro (c.256T>C) is very rare (popmax 0.00136%, afr) (gnomAD).

What do computational predictors say about CNTN2 p.Ser86Pro (c.256T>C)?

AlphaMissense predicts likely pathogenic (score 0.6246) — an in-silico prediction, not a clinical call.

CNTN2 p.Ser86Pro

c.256T>C · rs140567763 · VCV966634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6246 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, familial adult myoclonic, 5

Computational evidence

Protein change
AlphaMissense	0.6246	likely pathogenic
REVEL	0.047	moderately benign-leaning
SaProt	LLR -13.71	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.65 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 21 kb · p 1.7e-15 · regional, not allelic
Overall
CADD	19.83	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 0.00136% African / African-American · 1/73,726 alleles

Overall 0.000658% 1/152,078 alleles · very rare

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.Ser86Pro
Coding: c.256T>C
MANE Select: NM_005076
dbSNP: rs140567763
Type: single nucleotide variant
Location: chr1:205058221 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 86.13 · 5 PDB
Residue 86: a disulfide bond; the ig-like c2-type 1 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 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-ser86pro (accessed [today's date]).

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