Is CNTNAP1 p.Leu6Pro (c.17T>C) pathogenic?

CNTNAP1 p.Leu6Pro (c.17T>C) is classified Uncertain significance in CNTNAP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-16). AlphaMissense: likely benign (0.1233); Rare (popmax 0.125%, afr).

How common is CNTNAP1 p.Leu6Pro (c.17T>C) in the general population?

CNTNAP1 p.Leu6Pro (c.17T>C) is rare (popmax 0.125%, afr) (gnomAD).

What do computational predictors say about CNTNAP1 p.Leu6Pro (c.17T>C)?

AlphaMissense predicts likely benign (score 0.1233) — an in-silico prediction, not a clinical call.

CNTNAP1 p.Leu6Pro

c.17T>C · rs144595361 · VCV1919335

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1233 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.125%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1233	likely benign
REVEL	0.589	indeterminate
SaProt	LLR -10.58	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.94, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,091 bp · p 0.69 · regional, not allelic
Overall
CADD	23.3	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

Grpmax group 0.125% African / African-American · 93/74,500 alleles

Filtering AF 0.104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0967%

Overall 0.00616% 98/1,590,610 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.125%	801
Remaining individualsnot grpmax-eligible	0.00487%	20,531
Admixed American	0.00351%	28,528

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.Leu6Pro
Coding: c.17T>C
MANE Select: NM_003632
dbSNP: rs144595361
Type: single nucleotide variant
Location: chr17:42682846 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51

Full CNTNAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNTNAP1 p.Arg1121Ter Pathogenic ★★ same type
CNTNAP1 p.Arg618Ter Pathogenic/Likely pathogenic ★★ same type
CNTNAP1 p.Arg697Ter Pathogenic/Likely pathogenic ★★ same type
CNTNAP1 p.Arg835Ter Pathogenic ★★ same type
CNTNAP1 p.Arg890Ter Pathogenic ★★ same type
CNTNAP1 p.Trp672Ter Pathogenic ★★ same type
CNTNAP1 c.3568+10G>A Uncertain significance ★★ same type
CNTNAP1 p.Ala1322Thr Uncertain significance ★★ ⚠ same type

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-leu6pro (accessed [today's date]).

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