Is CNTNAP2 p.Ser367Pro (c.1099T>C) pathogenic?

CNTNAP2 p.Ser367Pro (c.1099T>C) is classified Uncertain significance in CNTNAP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.4963); Very rare (popmax 0.0022%, sas); Associated with cortical dysplasia-focal epilepsy syndrome.

What condition is associated with CNTNAP2 p.Ser367Pro (c.1099T>C)?

CNTNAP2 p.Ser367Pro (c.1099T>C) is associated with cortical dysplasia-focal epilepsy syndrome (ClinVar).

How common is CNTNAP2 p.Ser367Pro (c.1099T>C) in the general population?

CNTNAP2 p.Ser367Pro (c.1099T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CNTNAP2 p.Ser367Pro (c.1099T>C)?

AlphaMissense predicts ambiguous (score 0.4963) — an in-silico prediction, not a clinical call.

CNTNAP2 p.Ser367Pro

Q: How is CNTNAP2-related developmental and epileptic encephalopathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1099T>C · rs564865065 · VCV205231

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

cortical dysplasia-focal epilepsy syndrome

Computational evidence

Protein change
AlphaMissense	0.4963	ambiguous
REVEL	0.524	indeterminate
SaProt	LLR -10.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,299 kb · p 0.34 · regional, not allelic
Overall
CADD	22.2	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 0.0022% South Asian · 2/91,078 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,613,698 alleles · very rare exomes 1/1,461,490 · genomes 1/152,208 · joint denominator

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: CNTNAP2
Protein: p.Ser367Pro
Coding: c.1099T>C
MANE Select: NM_014141
dbSNP: rs564865065
Type: single nucleotide variant
Location: chr7:147132260 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.81 · 1 PDB
Residue 367: the laminin g-like 1 domain

Full CNTNAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cortical dysplasia-focal epilepsy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CNTNAP2-related developmental and epileptic encephalopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

CNTNAP2 p.Ser367= Likely benign ★★ same residue
CNTNAP2 p.Ser367Phe Uncertain significance ★ ⚠ same residue
CNTNAP2 c.1348+1G>A Likely pathogenic ★★ same condition
CNTNAP2 c.3382-2A>C Likely pathogenic ★★ same condition
CNTNAP2 c.97+1G>A Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 p.Arg1088Ter Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 p.Arg1095Ter Pathogenic/Likely pathogenic ★★ same condition
CNTNAP2 p.Arg483Ter Pathogenic/Likely pathogenic ★★ 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/cntnap2-p-ser367pro (accessed [today's date]).

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