Is CNTN1 p.Ser221Arg (c.663C>G) pathogenic?

CNTN1 p.Ser221Arg (c.663C>G) is classified Uncertain significance in CNTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-17). AlphaMissense: likely pathogenic (0.7687); Absent from gnomAD v4.1; Associated with Compton-North congenital myopathy.

What condition is associated with CNTN1 p.Ser221Arg (c.663C>G)?

CNTN1 p.Ser221Arg (c.663C>G) is associated with Compton-North congenital myopathy (ClinVar).

How common is CNTN1 p.Ser221Arg (c.663C>G) in the general population?

CNTN1 p.Ser221Arg (c.663C>G) is absent from gnomAD v4.1 (gnomAD).

How is Congenital lethal myopathy, Compton-North type inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CNTN1 p.Ser221Arg (c.663C>G)?

AlphaMissense predicts likely pathogenic (score 0.7687) — an in-silico prediction, not a clinical call.

CNTN1 p.Ser221Arg

c.663C>G · rs1437685014 · VCV1713620

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7687 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Compton-North congenital myopathy

Computational evidence

Protein change
AlphaMissense	0.7687	likely pathogenic
REVEL	0.491	indeterminate
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.042	GERP -0.86, phastCons 0.9
Regional constraint	o/e 0.81	unconstrained · MANE · 162 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	19.38	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CNTN1
Protein: p.Ser221Arg
Coding: c.663C>G
MANE Select: NM_001843
dbSNP: rs1437685014
Type: single nucleotide variant
Location: chr12:40929962 (GRCh38)
Gene constraint: LOEUF 0.431 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.29 · 2 PDB
Residue 221: the ig-like c2-type 2 domain; a β-strand

Full CNTN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Compton-North congenital myopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital lethal myopathy, Compton-North type (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

CNTN1 p.Ala410Val Uncertain significance ★★ ⚠ same condition
CNTN1 p.Ala514Thr Uncertain significance ★★ ⚠ same condition
CNTN1 p.Ala528Val Uncertain significance ★★ ⚠ same condition
CNTN1 p.Ala668Thr Uncertain significance ★★ ⚠ same condition
CNTN1 p.Ala799Thr Uncertain significance ★★ ⚠ same condition
CNTN1 p.Ala930Ser Uncertain significance ★★ ⚠ same condition
CNTN1 p.Ala995Thr Uncertain significance ★★ ⚠ same condition
CNTN1 p.Arg274Gln 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/cntn1-p-ser221arg (accessed [today's date]).

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