Is CNTN1 p.Ser775Arg (c.2325C>A) pathogenic?

CNTN1 p.Ser775Arg (c.2325C>A) is classified Uncertain significance in CNTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-26). AlphaMissense: ambiguous (0.4229); Ultra-rare (popmax 0.0107%, afr); Associated with Compton-North congenital myopathy.

What condition is associated with CNTN1 p.Ser775Arg (c.2325C>A)?

CNTN1 p.Ser775Arg (c.2325C>A) is associated with Compton-North congenital myopathy (ClinVar).

How common is CNTN1 p.Ser775Arg (c.2325C>A) in the general population?

CNTN1 p.Ser775Arg (c.2325C>A) is ultra-rare (popmax 0.0107%, afr) (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.Ser775Arg (c.2325C>A)?

AlphaMissense predicts ambiguous (score 0.4229) — an in-silico prediction, not a clinical call.

CNTN1 p.Ser775Arg

c.2325C>A · rs538201110 · VCV1465977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4229 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Compton-North congenital myopathy

Computational evidence

Protein change
AlphaMissense	0.4229	ambiguous
REVEL	0.103	moderately benign-leaning
SaProt	LLR -6.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.74	GERP -0.81, phastCons 0.003
Regional constraint	o/e 0.81	unconstrained · MANE · 162 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	14.75	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 0.0107% African / African-American · 8/75,050 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000558% 9/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,381
Finnishnot grpmax-eligible	0.00156%	64,032

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: CNTN1
Protein: p.Ser775Arg
Coding: c.2325C>A
MANE Select: NM_001843
dbSNP: rs538201110
Type: single nucleotide variant
Location: chr12:41016822 (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 775: the fibronectin type-iii 2 domain

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.Ser775Asn Benign ★★ same residue
CNTN1 p.Ser775Ile Uncertain significance ★ ⚠ same residue
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

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-ser775arg (accessed [today's date]).

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