Is CCN2 p.Pro76Leu (c.227C>T) pathogenic?

CCN2 p.Pro76Leu (c.227C>T) is classified Uncertain significance in CCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely benign (0.1366); Very rare (popmax 0.00409%, afr).

How common is CCN2 p.Pro76Leu (c.227C>T) in the general population?

CCN2 p.Pro76Leu (c.227C>T) is very rare (popmax 0.00409%, afr) (gnomAD).

What do computational predictors say about CCN2 p.Pro76Leu (c.227C>T)?

AlphaMissense predicts likely benign (score 0.1366) — an in-silico prediction, not a clinical call.

CCN2 p.Pro76Leu

c.227C>T · rs778832399 · VCV3139783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1366 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00409%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1366	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -8.49	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 8.3	GERP -1.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,905 bp · p 0.18 · regional, not allelic
Overall
CADD	25.7	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 0.00409% African / African-American · 3/73,366 alleles

Filtering AF 0.00125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00187% 26/1,387,102 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00409%	24,455
European (non-Finnish)	0.00191%	52,253
Remaining individualsnot grpmax-eligible	0.00167%	60,036

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.Pro76Leu
Coding: c.227C>T
MANE Select: NM_001901
dbSNP: rs778832399
Type: single nucleotide variant
Location: chr6:131950832 (GRCh38)
Gene constraint: LOEUF 1.05 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.43
Residue 76: 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-pro76leu (accessed [today's date]).

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