Is CNTN2 p.Arg235Trp (c.703C>T) pathogenic?

CNTN2 p.Arg235Trp (c.703C>T) is classified Conflicting classifications of pathogenicity in CNTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-16). AlphaMissense: likely benign (0.3035); Very rare (popmax 0.00333%, amr); Associated with epilepsy, familial adult myoclonic, 5.

What condition is associated with CNTN2 p.Arg235Trp (c.703C>T)?

CNTN2 p.Arg235Trp (c.703C>T) is associated with epilepsy, familial adult myoclonic, 5 (ClinVar).

How common is CNTN2 p.Arg235Trp (c.703C>T) in the general population?

CNTN2 p.Arg235Trp (c.703C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CNTN2 p.Arg235Trp (c.703C>T)?

AlphaMissense predicts likely benign (score 0.3035) — an in-silico prediction, not a clinical call.

CNTN2 p.Arg235Trp

c.703C>T · rs747208674 · VCV1590960

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

epilepsy, familial adult myoclonic, 5

Computational evidence

Protein change
AlphaMissense	0.3035	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.41, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 21 kb · p 1.7e-15 · regional, not allelic
Overall
CADD	25.8	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 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00372% 60/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0297%	3,371
Remaining individualsnot grpmax-eligible	0.0096%	10,414
Admixed Americangrpmax	0.00333%	30,004
African / African-American	0.00267%	37,444
European (non-Finnish)	0.00254%	39,333
South Asian	0.0011%	91,088

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: CNTN2
Protein: p.Arg235Trp
Coding: c.703C>T
MANE Select: NM_005076
dbSNP: rs747208674
Type: single nucleotide variant
Location: chr1:205059588 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 86.13 · 5 PDB

Full CNTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

epilepsy, familial adult myoclonic, 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CNTN2 p.Arg235Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CNTN2 c.1241-1G>C Likely pathogenic ★★ same condition
CNTN2 c.2432-2A>G Likely pathogenic ★★ same condition
CNTN2 p.Arg140Ter Pathogenic/Likely pathogenic ★★ same condition
CNTN2 p.Arg314Ter Pathogenic ★★ same condition
CNTN2 p.Trp731Ter Pathogenic/Likely pathogenic ★★ same condition
CNTN2 c.2196+5G>A Uncertain significance ★★ same condition
CNTN2 p.Ala230Val 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/cntn2-p-arg235trp (accessed [today's date]).

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