Is CNTNAP1 p.Pro1357Ser (c.4069C>T) pathogenic?

CNTNAP1 p.Pro1357Ser (c.4069C>T) is classified Uncertain significance in CNTNAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-20). AlphaMissense: likely benign (0.0745); Very rare (popmax 0.00893%, eas); Associated with Inborn genetic diseases.

What condition is associated with CNTNAP1 p.Pro1357Ser (c.4069C>T)?

CNTNAP1 p.Pro1357Ser (c.4069C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CNTNAP1 p.Pro1357Ser (c.4069C>T) in the general population?

CNTNAP1 p.Pro1357Ser (c.4069C>T) is very rare (popmax 0.00893%, eas) (gnomAD).

What do computational predictors say about CNTNAP1 p.Pro1357Ser (c.4069C>T)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

CNTNAP1 p.Pro1357Ser

c.4069C>T · rs781030048 · VCV2215920

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00893%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -7.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.28	GERP 0.47, phastCons 0.01
Regional constraint	o/e 0.78	unconstrained · MANE · 15 kb · p 9.7e-20 · regional, not allelic
Overall
CADD	11.07	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00893% East Asian · 4/44,792 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000312% 5/1,602,546 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00893%	11,198
European (non-Finnish)	8.49e-05%	1,178,468

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: CNTNAP1
Protein: p.Pro1357Ser
Coding: c.4069C>T
MANE Select: NM_003632
dbSNP: rs781030048
Type: single nucleotide variant
Location: chr17:42698824 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 1357: the 'disordered' region; a UniProt-annotated variant site (in chn3); a UniProt-annotated variant site (in lccs7 and chn3); a UniProt-annotated variant site (in lccs7)

Full CNTNAP1 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

Similar variants

CNTNAP1 p.Ala1322Thr Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Ala254Thr Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Ala40Thr Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Ala887Val Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1022Ser Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1073His Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1150Cys Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1153Gln 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/cntnap1-p-pro1357ser (accessed [today's date]).

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