Is CNTNAP1 p.Arg1121Ter (c.3361C>T) pathogenic?

CNTNAP1 p.Arg1121Ter (c.3361C>T) is classified Pathogenic in CNTNAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-25). Ultra-rare (popmax 0.0164%, mid); Associated with neuropathy, congenital hypomyelinating, 3.

What condition is associated with CNTNAP1 p.Arg1121Ter (c.3361C>T)?

CNTNAP1 p.Arg1121Ter (c.3361C>T) is associated with neuropathy, congenital hypomyelinating, 3, lethal congenital contracture syndrome 7 (ClinVar).

How common is CNTNAP1 p.Arg1121Ter (c.3361C>T) in the general population?

CNTNAP1 p.Arg1121Ter (c.3361C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

CNTNAP1 p.Arg1121Ter

c.3361C>T · rs142756549 · VCV1219168

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

neuropathy, congenital hypomyelinating, 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 20 of 24
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.007, phastCons 1
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,613,980 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00167%	59,996
European (non-Finnish)	0.000678%	147,503

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.Arg1121Ter
Coding: c.3361C>T
MANE Select: NM_003632
dbSNP: rs142756549
Type: single nucleotide variant
Location: chr17:42696039 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 1121: the laminin g-like 4 domain; a UniProt-annotated variant site (in chn3); a UniProt-annotated variant site (in lccs7 and chn3); a UniProt-annotated variant site (in lccs7)

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

Also linked: lethal congenital contracture syndrome 7

Similar variants

CNTNAP1 p.Arg1121Gln Uncertain significance ★★ ⚠ same residue
CNTNAP1 p.Arg1121= Likely benign ★★ same residue
CNTNAP1 p.Arg697Ter Pathogenic/Likely pathogenic ★★ same condition
CNTNAP1 p.Arg835Ter Pathogenic ★★ same condition
CNTNAP1 p.Arg890Ter Pathogenic ★★ same condition
CNTNAP1 p.Trp672Ter Pathogenic ★★ same condition
CNTNAP1 p.Arg1073His Uncertain significance ★★ ⚠ same condition
CNTNAP1 p.Arg1187His Uncertain significance ★★ ⚠ 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-arg1121ter (accessed [today's date]).

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