Is CNTN2 p.Pro162Ser (c.484C>T) pathogenic?

CNTN2 p.Pro162Ser (c.484C>T) is classified Uncertain significance in CNTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.6042); Very rare (popmax 8.48e-05%, nfe).

How common is CNTN2 p.Pro162Ser (c.484C>T) in the general population?

CNTN2 p.Pro162Ser (c.484C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CNTN2 p.Pro162Ser (c.484C>T)?

AlphaMissense predicts likely pathogenic (score 0.6042) — an in-silico prediction, not a clinical call.

CNTN2 p.Pro162Ser

c.484C>T · VCV4655091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6042 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6042	likely pathogenic
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -11.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 21 kb · p 1.7e-15 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,412 alleles

Overall 6.2e-05% 1/1,613,022 alleles · very rare exomes 1/1,460,806 · genomes 0/152,216 · joint denominator

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.Pro162Ser
Coding: c.484C>T
MANE Select: NM_005076
Type: single nucleotide variant
Location: chr1:205058660 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 86.13 · 5 PDB
Residue 162: the ig-like c2-type 2 domain; a β-strand

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

Similar variants

CNTN2 p.Pro162= Benign ★★ same residue
CNTN2 c.1241-1G>C Likely pathogenic ★★ same type
CNTN2 c.2432-2A>G Likely pathogenic ★★ same type
CNTN2 p.Arg140Ter Pathogenic/Likely pathogenic ★★ same type
CNTN2 p.Arg314Ter Pathogenic ★★ same type
CNTN2 p.Trp731Ter Pathogenic/Likely pathogenic ★★ same type
CNTN2 c.2196+5G>A Uncertain significance ★★ same type
CNTN2 p.Ala230Val Uncertain significance ★★ ⚠ same type

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-pro162ser (accessed [today's date]).

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