Is CNTNAP1 p.Val522Leu (c.1564G>C) pathogenic?

CNTNAP1 p.Val522Leu (c.1564G>C) is classified Benign in CNTNAP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1621); Common (popmax 12.3%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CNTNAP1 p.Val522Leu (c.1564G>C)?

AlphaMissense predicts likely benign (score 0.1621) — an in-silico prediction, not a clinical call.

CNTNAP1 p.Val522Leu

Q: How common is CNTNAP1 p.Val522Leu (c.1564G>C) in the general population?

CNTNAP1 p.Val522Leu (c.1564G>C) is common (popmax 12.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1564G>C · rs35437096 · VCV1166722

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1621 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1621	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 15 kb · p 9.7e-20 · regional, not allelic
Overall
CADD	22.1	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 12.3% African / African-American · 9,236/74,912 alleles

Filtering AF 12.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 12%

Overall 0.693% 11,177/1,613,082 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.3%	8
Ashkenazi Jewishnot grpmax-eligible	1.01%	99
Admixed American	0.945%	106
Remaining individualsnot grpmax-eligible	0.873%	115
Middle Eastern	0.71%	141
European (non-Finnish)	0.0393%	2,542
Finnishnot grpmax-eligible	0.0172%	5,820
South Asian	0.0143%	6,997

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.Val522Leu
Coding: c.1564G>C
MANE Select: NM_003632
dbSNP: rs35437096
Type: single nucleotide variant
Location: chr17:42688983 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 522: a disulfide bond; a UniProt-annotated variant site (in); the laminin g-like 2 domain

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

Similar variants

CNTNAP1 p.Val522Ala Uncertain significance ★ ⚠ same residue
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

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-val522leu (accessed [today's date]).

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