Is CCN5 p.Pro146Arg (c.437C>G) pathogenic?

CCN5 p.Pro146Arg (c.437C>G) is classified Uncertain significance in CCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-07). AlphaMissense: likely benign (0.1338); Absent from gnomAD v4.1.

How common is CCN5 p.Pro146Arg (c.437C>G) in the general population?

CCN5 p.Pro146Arg (c.437C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCN5 p.Pro146Arg (c.437C>G)?

AlphaMissense predicts likely benign (score 0.1338) — an in-silico prediction, not a clinical call.

CCN5 p.Pro146Arg

c.437C>G · VCV3487336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1338 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1338	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -12.43	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.19 · regional, not allelic
Overall
CADD	26.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCN5
Protein: p.Pro146Arg
Coding: c.437C>G
MANE Select: NM_003881
Type: single nucleotide variant
Location: chr20:44724897 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.59
Residue 146: the vwfc 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.Arg215Trp Uncertain significance ★ ⚠ same type
CCN5 p.Arg221His Uncertain significance ★ ⚠ same type
CCN5 p.Arg229Cys 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-pro146arg (accessed [today's date]).

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