Is CNTNAP2 p.Pro76Ser (c.226C>T) pathogenic?

CNTNAP2 p.Pro76Ser (c.226C>T) is classified Uncertain significance in CNTNAP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-22). AlphaMissense: likely pathogenic (0.8613); Very rare (popmax 0.00667%, afr); Associated with Inborn genetic diseases.

What condition is associated with CNTNAP2 p.Pro76Ser (c.226C>T)?

CNTNAP2 p.Pro76Ser (c.226C>T) is associated with Inborn genetic diseases, cortical dysplasia-focal epilepsy syndrome (ClinVar).

How common is CNTNAP2 p.Pro76Ser (c.226C>T) in the general population?

CNTNAP2 p.Pro76Ser (c.226C>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about CNTNAP2 p.Pro76Ser (c.226C>T)?

AlphaMissense predicts likely pathogenic (score 0.8613) — an in-silico prediction, not a clinical call.

CNTNAP2 p.Pro76Ser

c.226C>T · rs149632465 · VCV1369652

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8613	likely pathogenic
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -13.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 2,299 kb · p 0.34 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% African / African-American · 5/74,930 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000434% 7/1,614,078 alleles · very rare exomes 5/1,461,868 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,986
Admixed American	0.00333%	30,002

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.Pro76Ser
Coding: c.226C>T
MANE Select: NM_014141
dbSNP: rs149632465
Type: single nucleotide variant
Location: chr7:146839728 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 83.81 · 1 PDB
Residue 76: the f5/8 type c domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cortical dysplasia-focal epilepsy syndrome

Similar variants

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
CNTNAP2 p.Gln297Ter 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-pro76ser (accessed [today's date]).

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