Is CNTNAP2 p.Pro320Arg (c.959C>G) pathogenic?

CNTNAP2 p.Pro320Arg (c.959C>G) is classified Uncertain significance in CNTNAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-26). AlphaMissense: ambiguous (0.3539); Very rare (popmax 0.00267%, afr); Associated with cortical dysplasia-focal epilepsy syndrome.

What condition is associated with CNTNAP2 p.Pro320Arg (c.959C>G)?

CNTNAP2 p.Pro320Arg (c.959C>G) is associated with cortical dysplasia-focal epilepsy syndrome (ClinVar).

How common is CNTNAP2 p.Pro320Arg (c.959C>G) in the general population?

CNTNAP2 p.Pro320Arg (c.959C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CNTNAP2 p.Pro320Arg (c.959C>G)?

AlphaMissense predicts ambiguous (score 0.3539) — an in-silico prediction, not a clinical call.

CNTNAP2 p.Pro320Arg

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.959C>G · rs765754117 · VCV2119482

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3539 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

cortical dysplasia-focal epilepsy syndrome

Computational evidence

Protein change
AlphaMissense	0.3539	ambiguous
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -8.61	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,299 kb · p 0.34 · regional, not allelic
Overall
CADD	28.4	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 0.00267% African / African-American · 2/74,894 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,613,886 alleles · very rare exomes 3/1,461,736 · genomes 1/152,150 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,447
East Asian	0.00223%	44,880
European (non-Finnish)	8.48e-05%	1,179,934

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.Pro320Arg
Coding: c.959C>G
MANE Select: NM_014141
dbSNP: rs765754117
Type: single nucleotide variant
Location: chr7:147128712 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.81 · 1 PDB
Residue 320: 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.Pro320Ser 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
CNTNAP2 p.Gln1111Ter 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-pro320arg (accessed [today's date]).

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