Is CNTN1 p.Pro137Ala (c.409C>G) pathogenic?

CNTN1 p.Pro137Ala (c.409C>G) is classified Uncertain significance in CNTN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-29). AlphaMissense: likely benign (0.1082); Ultra-rare (popmax 0.0167%, mid); Associated with Compton-North congenital myopathy.

What condition is associated with CNTN1 p.Pro137Ala (c.409C>G)?

CNTN1 p.Pro137Ala (c.409C>G) is associated with Compton-North congenital myopathy (ClinVar).

How common is CNTN1 p.Pro137Ala (c.409C>G) in the general population?

CNTN1 p.Pro137Ala (c.409C>G) is ultra-rare (popmax 0.0167%, mid) (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.Pro137Ala (c.409C>G)?

AlphaMissense predicts likely benign (score 0.1082) — an in-silico prediction, not a clinical call.

CNTN1 p.Pro137Ala

c.409C>G · rs765752838 · VCV2152818

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Compton-North congenital myopathy

Computational evidence

Protein change
AlphaMissense	0.1082	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -8.25	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 162 kb · p 1.2e-11 · regional, not allelic
Overall
CADD	19.47	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,974 alleles

Filtering AF 0.000369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000633% 9/1,421,534 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,974
South Asian	0.00222%	44,997
Remaining individualsnot grpmax-eligible	0.00164%	60,972
European (non-Finnish)	0.000437%	228,816

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.Pro137Ala
Coding: c.409C>G
MANE Select: NM_001843
dbSNP: rs765752838
Type: single nucleotide variant
Location: chr12:40924565 (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 137: the ig-like c2-type 2 domain; an α-helix

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.Pro137Leu 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
CNTN1 p.Ala995Thr 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-pro137ala (accessed [today's date]).

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