Is CNTN6 p.Arg595Lys (c.1784G>A) pathogenic?

CNTN6 p.Arg595Lys (c.1784G>A) is classified Uncertain significance in CNTN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.2081); Very rare (popmax 0.00027%, nfe).

How common is CNTN6 p.Arg595Lys (c.1784G>A) in the general population?

CNTN6 p.Arg595Lys (c.1784G>A) is very rare (popmax 0.00027%, nfe) (gnomAD).

What do computational predictors say about CNTN6 p.Arg595Lys (c.1784G>A)?

AlphaMissense predicts likely benign (score 0.2081) — an in-silico prediction, not a clinical call.

CNTN6 p.Arg595Lys

c.1784G>A · VCV4231206

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00027%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2081	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.34	unconstrained · MANE · 255 kb · p 8.2e-32 · regional, not allelic
Overall
CADD	24.7	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 0.00027% European (non-Finnish) · 3/1,110,390 alleles

Filtering AF 7.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000218% 3/1,379,294 alleles · very rare

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: CNTN6
Protein: p.Arg595Lys
Coding: c.1784G>A
MANE Select: NM_001289080
Type: single nucleotide variant
Location: chr3:1372953 (GRCh38)
Gene constraint: LOEUF 1.316 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 86.19

Full CNTN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNTN6 c.1213+8G>A Benign ★★ same type
CNTN6 p.Ala440Ser Benign ★★ same type
CNTN6 p.Arg135Ter Benign ★★ same type
CNTN6 p.Arg303Gln Likely benign ★★ same type
CNTN6 p.Gly1001= Benign/Likely benign ★★ same type
CNTN6 p.Gly96= Benign ★★ same type
CNTN6 p.Ile1024Leu Benign ★★ same type
CNTN6 p.Ile529Leu Benign/Likely benign ★★ 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/cntn6-p-arg595lys (accessed [today's date]).

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