Is CCN5 p.Arg215Trp (c.643C>T) pathogenic?

CCN5 p.Arg215Trp (c.643C>T) is classified Uncertain significance in CCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-04). AlphaMissense: ambiguous (0.5093); Ultra-rare (popmax 0.0107%, afr).

How common is CCN5 p.Arg215Trp (c.643C>T) in the general population?

CCN5 p.Arg215Trp (c.643C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about CCN5 p.Arg215Trp (c.643C>T)?

AlphaMissense predicts ambiguous (score 0.5093) — an in-silico prediction, not a clinical call.

CCN5 p.Arg215Trp

c.643C>T · rs763203992 · VCV3139836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5093	ambiguous
REVEL	0.858	moderately pathogenic-leaning
SaProt	LLR -12.00	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.19 · regional, not allelic
Overall
CADD	29.4	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 0.0107% African / African-American · 8/74,944 alleles

Filtering AF 0.00605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.00632% 102/1,613,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,368
European (non-Finnish)	0.00737%	13,564
East Asian	0.00668%	14,964
Remaining individualsnot grpmax-eligible	0.0048%	20,825
South Asian	0.0011%	91,082

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: CCN5
Protein: p.Arg215Trp
Coding: c.643C>T
MANE Select: NM_003881
dbSNP: rs763203992
Type: single nucleotide variant
Location: chr20:44727197 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.59
Residue 215: the tsp type-1 domain

Full CCN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN5 p.Leu169= Benign ★★ same type
CCN5 p.Ala11Asp Uncertain significance ★ same type
CCN5 p.Ala213Thr Uncertain significance ★ ⚠ same type
CCN5 p.Ala72Thr Uncertain significance ★ ⚠ same type
CCN5 p.Arg105Ser Uncertain significance ★ ⚠ same type
CCN5 p.Arg221His Uncertain significance ★ ⚠ same type
CCN5 p.Arg229Cys Uncertain significance ★ ⚠ same type
CCN5 p.Arg22His 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/ccn5-p-arg215trp (accessed [today's date]).

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