Is CCN2 p.Phe81Cys (c.242T>G) pathogenic?

CCN2 p.Phe81Cys (c.242T>G) is classified Uncertain significance in CCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: likely pathogenic (0.8771); Very rare (popmax 0.0068%, afr).

How common is CCN2 p.Phe81Cys (c.242T>G) in the general population?

CCN2 p.Phe81Cys (c.242T>G) is very rare (popmax 0.0068%, afr) (gnomAD).

What do computational predictors say about CCN2 p.Phe81Cys (c.242T>G)?

AlphaMissense predicts likely pathogenic (score 0.8771) — an in-silico prediction, not a clinical call.

CCN2 p.Phe81Cys

c.242T>G · VCV3997542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8771 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0068%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8771	likely pathogenic
REVEL	0.388	indeterminate
SaProt	LLR -9.67	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,905 bp · p 0.18 · regional, not allelic
Overall
CADD	24.4	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 0.0068% African / African-American · 5/73,526 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.000647% 10/1,545,096 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0068%	14,705
Remaining individualsnot grpmax-eligible	0.00332%	30,125
European (non-Finnish)	0.00026%	384,219

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.Phe81Cys
Coding: c.242T>G
MANE Select: NM_001901
Type: single nucleotide variant
Location: chr6:131950817 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.43
Residue 81: a disulfide bond; the igfbp n-terminal domain

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-phe81cys (accessed [today's date]).

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