Is CNTN2 p.Pro995Ser (c.2983C>T) pathogenic?

CNTN2 p.Pro995Ser (c.2983C>T) is classified Uncertain significance in CNTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-03). AlphaMissense: ambiguous (0.4749); Absent from gnomAD v4.1; Associated with epilepsy, familial adult myoclonic, 5.

What condition is associated with CNTN2 p.Pro995Ser (c.2983C>T)?

CNTN2 p.Pro995Ser (c.2983C>T) is associated with epilepsy, familial adult myoclonic, 5 (ClinVar).

How common is CNTN2 p.Pro995Ser (c.2983C>T) in the general population?

CNTN2 p.Pro995Ser (c.2983C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CNTN2 p.Pro995Ser (c.2983C>T)?

AlphaMissense predicts ambiguous (score 0.4749) — an in-silico prediction, not a clinical call.

CNTN2 p.Pro995Ser

c.2983C>T · rs1654685363 · VCV1028853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4749 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

epilepsy, familial adult myoclonic, 5

Computational evidence

Protein change
AlphaMissense	0.4749	ambiguous
REVEL	0.154	moderately benign-leaning
SaProt	LLR -9.89	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 21 kb · p 1.7e-15 · regional, not allelic
Overall
CADD	22.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNTN2
Protein: p.Pro995Ser
Coding: c.2983C>T
MANE Select: NM_005076
dbSNP: rs1654685363
Type: single nucleotide variant
Location: chr1:205073206 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 86.13 · 5 PDB
Residue 995: 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.Pro995= Likely benign ★★ 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-pro995ser (accessed [today's date]).

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