Is CCN3 p.Cys15Phe (c.44G>T) pathogenic?

CCN3 p.Cys15Phe (c.44G>T) is classified Benign in CCN3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0567); Low-frequency (popmax 1.72%, afr).

How common is CCN3 p.Cys15Phe (c.44G>T) in the general population?

CCN3 p.Cys15Phe (c.44G>T) is low-frequency (popmax 1.72%, afr) (gnomAD).

What do computational predictors say about CCN3 p.Cys15Phe (c.44G>T)?

AlphaMissense predicts likely benign (score 0.0567) — an in-silico prediction, not a clinical call.

CCN3 p.Cys15Phe

c.44G>T · rs35712802 · VCV775267

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0567 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.72%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0567	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -4.96	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 3.9	GERP -0.22, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 6,596 bp · p 0.65 · regional, not allelic
Overall
CADD	15.81	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 1.72% African / African-American · 1,290/75,064 alleles

Filtering AF 1.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.61%

Overall 0.214% 3,449/1,614,040 alleles · low-frequency

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.49%	40
African / African-Americangrpmax	1.72%	58
Middle Eastern	0.775%	129
Remaining individualsnot grpmax-eligible	0.4%	250
Admixed American	0.392%	255
European (non-Finnish)	0.0748%	1,336
Finnishnot grpmax-eligible	0.00468%	21,349
South Asian	0.0033%	30,331

Ashkenazi Jewish 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: CCN3
Protein: p.Cys15Phe
Coding: c.44G>T
MANE Select: NM_002514
dbSNP: rs35712802
Type: single nucleotide variant
Location: chr8:119416576 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88

Full CCN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN3 p.Ala157Asp Uncertain significance ★ ⚠ same type
CCN3 p.Ala187Ser Uncertain significance ★ ⚠ same type
CCN3 p.Ala51Ser Uncertain significance ★ ⚠ same type
CCN3 p.Arg143His Uncertain significance ★ ⚠ same type
CCN3 p.Arg227Trp Uncertain significance ★ ⚠ same type
CCN3 p.Arg233Cys Uncertain significance ★ ⚠ same type
CCN3 p.Arg299His Uncertain significance ★ ⚠ same type
CCN3 p.Arg34Pro 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/ccn3-p-cys15phe (accessed [today's date]).

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