Is CNTNAP1 p.Phe503Leu (c.1507T>C) pathogenic?

CNTNAP1 p.Phe503Leu (c.1507T>C) is classified Conflicting classifications of pathogenicity in CNTNAP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-03-24). AlphaMissense: likely pathogenic (0.9973); Very rare (popmax 0.00153%, nfe); Associated with neuropathy, congenital hypomyelinating, 3.

What condition is associated with CNTNAP1 p.Phe503Leu (c.1507T>C)?

CNTNAP1 p.Phe503Leu (c.1507T>C) is associated with neuropathy, congenital hypomyelinating, 3 (ClinVar).

How common is CNTNAP1 p.Phe503Leu (c.1507T>C) in the general population?

CNTNAP1 p.Phe503Leu (c.1507T>C) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about CNTNAP1 p.Phe503Leu (c.1507T>C)?

AlphaMissense predicts likely pathogenic (score 0.9973) — an in-silico prediction, not a clinical call.

CNTNAP1 p.Phe503Leu

c.1507T>C · rs373250430 · VCV1929512

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9973 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuropathy, congenital hypomyelinating, 3

Computational evidence

Protein change
AlphaMissense	0.9973	likely pathogenic · top 4% in CNTNAP1
REVEL	0.833	moderately pathogenic-leaning
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 15 kb · p 9.7e-20 · regional, not allelic
Overall
CADD	27.2	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 0.00153% European (non-Finnish) · 18/1,180,008 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,613,998 alleles · very rare

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.Phe503Leu
Coding: c.1507T>C
MANE Select: NM_003632
dbSNP: rs373250430
Type: single nucleotide variant
Location: chr17:42688926 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 503: the laminin g-like 2 domain

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

Disease context

neuropathy, congenital hypomyelinating, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNTNAP1 p.Arg1121Ter Pathogenic ★★ same condition
CNTNAP1 p.Arg697Ter Pathogenic/Likely pathogenic ★★ same condition
CNTNAP1 p.Arg835Ter Pathogenic ★★ same condition
CNTNAP1 p.Trp672Ter Pathogenic ★★ same condition
CNTNAP1 p.Arg1073His Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1187His Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Thr569Met Uncertain significance ★★ ⚠ same condition
CNTNAP1 c.1736-22G>A Benign ★★ 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-phe503leu (accessed [today's date]).

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