Is CCN1 c.277+50G>C pathogenic?

CCN1 c.277+50G>C is classified Benign in CCN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-11-12). Common (popmax 23.6%, amr) — too common for a highly-penetrant pathogenic allele.

CCN1 c.277+50G>C

Q: How common is CCN1 c.277+50G>C in the general population?

CCN1 c.277+50G>C is common (popmax 23.6%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs9658584 · VCV1178850

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 23.6%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +50	near-intronic (+50 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Non-coding constraint	Z 2.96	1 kb window · o/e 0.71 · regional · uncalibrated
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23.6% Admixed American · 13,267/56,106 alleles

Filtering AF 23.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 23.2%

Overall 19.3% 303,264/1,573,466 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	29.3%	3
Admixed Americangrpmax	23.6%	4
Middle Eastern	22.4%	4
European (non-Finnish)	20.6%	5
Remaining individualsnot grpmax-eligible	18.8%	5
Ashkenazi Jewishnot grpmax-eligible	18.1%	6
Finnishnot grpmax-eligible	16.2%	6
South Asian	16%	6
East Asian	14.3%	7
African / African-American	4.82%	21

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CCN1
Coding: c.277+50G>C
MANE Select: NM_001237 · reported on NM_001554
dbSNP: rs9658584
Type: single nucleotide variant
Location: chr1:85581628 (GRCh38)
Structure: AlphaFold pLDDT 73.80 · 115 PDB

Full CCN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOSC9 p.Ala438Val Uncertain significance ★★ ⚠ same type
CCN1 c.64-124G>A Benign ★★ same type
CCN1 c.-107C>A Benign ★★ same type
CCN1 p.Ser316Cys Likely benign ★★ ⚠ same type
CCN1 p.Tyr300= Benign ★★ same type
CCNA2 c.*828C>G Benign ★★ same type
CCNA2 p.Leu126= Benign ★★ same type
CCNA2 p.Lys112Glu 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/ccn1-c-277-plus-50g-c (accessed [today's date]).

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