Is CNTNAP1 p.Arg697Ter (c.2089C>T) pathogenic?

CNTNAP1 p.Arg697Ter (c.2089C>T) is classified Pathogenic/Likely pathogenic in CNTNAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-16). Very rare (popmax 0.0011%, sas); Associated with neuropathy, congenital hypomyelinating, 3.

What condition is associated with CNTNAP1 p.Arg697Ter (c.2089C>T)?

CNTNAP1 p.Arg697Ter (c.2089C>T) is associated with neuropathy, congenital hypomyelinating, 3 (ClinVar).

How common is CNTNAP1 p.Arg697Ter (c.2089C>T) in the general population?

CNTNAP1 p.Arg697Ter (c.2089C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

CNTNAP1 p.Arg697Ter

c.2089C>T · rs2543797507 · VCV2439167

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

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 14 of 24
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.70 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.6	GERP -0.63, 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 0.0011% South Asian · 1/91,074 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000342% 5/1,461,824 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,030
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	0.000254%	393,335

Finnish 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.Arg697Ter
Coding: c.2089C>T
MANE Select: NM_003632
dbSNP: rs2543797507
Type: single nucleotide variant
Location: chr17:42691166 (GRCh38)
Gene constraint: LOEUF 0.578 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 697: a UniProt-annotated variant site (in chn3); a UniProt-annotated variant site (in lccs7 and chn3); a UniProt-annotated variant site (in lccs7); the fibrinogen c-terminal 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.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
CNTNAP1 c.364-34A>G 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-arg697ter (accessed [today's date]).

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