Is CCN2 p.Lys252Glu (c.754A>G) pathogenic?

CCN2 p.Lys252Glu (c.754A>G) is classified Uncertain significance in CCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-26). AlphaMissense: likely benign (0.2905); Very rare (popmax 0.00386%, nfe).

How common is CCN2 p.Lys252Glu (c.754A>G) in the general population?

CCN2 p.Lys252Glu (c.754A>G) is very rare (popmax 0.00386%, nfe) (gnomAD).

What do computational predictors say about CCN2 p.Lys252Glu (c.754A>G)?

AlphaMissense predicts likely benign (score 0.2905) — an in-silico prediction, not a clinical call.

CCN2 p.Lys252Glu

c.754A>G · VCV4221983

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2905 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00386%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2905	likely benign
REVEL	0.512	indeterminate
SaProt	LLR -10.15	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.70	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 6.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,905 bp · p 0.18 · regional, not allelic
Overall
CADD	28.7	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 0.00386% European (non-Finnish) · 45/1,166,626 alleles

Filtering AF 0.00294% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00262%

Overall 0.00312% 45/1,443,398 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: CCN2
Protein: p.Lys252Glu
Coding: c.754A>G
MANE Select: NM_001901
Type: single nucleotide variant
Location: chr6:131949560 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.43
Residue 252: the 'heparin-binding' region

Full CCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN2 c.290-6C>T Benign ★★ same type
CCN2 c.67-4G>A Likely benign ★★ same type
CCN2 p.Ala101Ser Uncertain significance ★ ⚠ same type
CCN2 p.Ala208Thr Uncertain significance ★ ⚠ same type
CCN2 p.Ala45Val Uncertain significance ★ ⚠ same type
CCN2 p.Ala61Thr Uncertain significance ★ ⚠ same type
CCN2 p.Arg34Gly Uncertain significance ★ ⚠ same type
CCN2 p.Arg42Gly 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/ccn2-p-lys252glu (accessed [today's date]).

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