Is CNTN1 p.Pro776Ser (c.2326C>T) pathogenic?

CNTN1 p.Pro776Ser (c.2326C>T) is classified Conflicting classifications of pathogenicity in CNTN1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-21). AlphaMissense: likely benign (0.2043); Ultra-rare (popmax 0.035%, amr); Associated with Inborn genetic diseases.

What condition is associated with CNTN1 p.Pro776Ser (c.2326C>T)?

CNTN1 p.Pro776Ser (c.2326C>T) is associated with Inborn genetic diseases, Compton-North congenital myopathy (ClinVar).

How common is CNTN1 p.Pro776Ser (c.2326C>T) in the general population?

CNTN1 p.Pro776Ser (c.2326C>T) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about CNTN1 p.Pro776Ser (c.2326C>T)?

AlphaMissense predicts likely benign (score 0.2043) — an in-silico prediction, not a clinical call.

CNTN1 p.Pro776Ser

c.2326C>T · rs199833589 · VCV958274

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2043 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2043	likely benign
REVEL	0.431	indeterminate
SaProt	LLR -6.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 162 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	24.3	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 0.035% Admixed American · 21/60,016 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00136% 22/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,858
European (non-Finnish)	8.47e-05%	1,179,998

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.Pro776Ser
Coding: c.2326C>T
MANE Select: NM_001843
dbSNP: rs199833589
Type: single nucleotide variant
Location: chr12:41016823 (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 776: the fibronectin type-iii 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Compton-North congenital myopathy

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-pro776ser (accessed [today's date]).

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