Is CNTNAP1 p.Glu446Lys (c.1336G>A) pathogenic?

CNTNAP1 p.Glu446Lys (c.1336G>A) is classified Uncertain significance in CNTNAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-29). AlphaMissense: likely benign (0.1825); Very rare (popmax 0.00267%, afr).

How common is CNTNAP1 p.Glu446Lys (c.1336G>A) in the general population?

CNTNAP1 p.Glu446Lys (c.1336G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CNTNAP1 p.Glu446Lys (c.1336G>A)?

AlphaMissense predicts likely benign (score 0.1825) — an in-silico prediction, not a clinical call.

CNTNAP1 p.Glu446Lys

c.1336G>A · rs1203537396 · VCV1916978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1825	likely benign
REVEL	0.4	indeterminate
SaProt	LLR -5.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.81 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 15 kb · p 9.7e-20 · regional, not allelic
Overall
CADD	25.0	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 0.00267% African / African-American · 2/75,024 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,182 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,512
Admixed American	0.00167%	60,020
European (non-Finnish)	8.47e-05%	1,180,045

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.Glu446Lys
Coding: c.1336G>A
MANE Select: NM_003632
dbSNP: rs1203537396
Type: single nucleotide variant
Location: chr17:42688491 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 446: the laminin g-like 2 domain

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-glu446lys (accessed [today's date]).

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