Is CNTNAP1 p.Leu212Pro (c.635T>C) pathogenic?

CNTNAP1 p.Leu212Pro (c.635T>C) is classified Pathogenic in CNTNAP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-11-27). AlphaMissense: likely pathogenic (0.9868); Very rare (popmax 0.000339%, nfe); Associated with neuropathy, congenital hypomyelinating, 3.

What condition is associated with CNTNAP1 p.Leu212Pro (c.635T>C)?

CNTNAP1 p.Leu212Pro (c.635T>C) is associated with neuropathy, congenital hypomyelinating, 3 (ClinVar).

How common is CNTNAP1 p.Leu212Pro (c.635T>C) in the general population?

CNTNAP1 p.Leu212Pro (c.635T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CNTNAP1 p.Leu212Pro (c.635T>C)?

AlphaMissense predicts likely pathogenic (score 0.9868) — an in-silico prediction, not a clinical call.

CNTNAP1 p.Leu212Pro

c.635T>C · rs1567969825 · VCV590912

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuropathy, congenital hypomyelinating, 3

Computational evidence

Protein change
AlphaMissense	0.9868	likely pathogenic ✓ concordant with ClinVar
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -14.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 15 kb · p 9.7e-20 · regional, not allelic
Overall
CADD	26.1	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 0.000339% European (non-Finnish) · 4/1,179,986 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000343% 5/1,458,764 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)grpmax	0.000339%	294,997

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu212Pro
Coding: c.635T>C
MANE Select: NM_003632
dbSNP: rs1567969825
Type: single nucleotide variant
Location: chr17:42685340 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 212: a UniProt-annotated variant site (in chn3); the laminin g-like 1 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-leu212pro (accessed [today's date]).

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