Is CCN3 p.Arg299His (c.896G>A) pathogenic?

CCN3 p.Arg299His (c.896G>A) is classified Uncertain significance in CCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: ambiguous (0.3833); Rare (popmax 0.122%, amr).

How common is CCN3 p.Arg299His (c.896G>A) in the general population?

CCN3 p.Arg299His (c.896G>A) is rare (popmax 0.122%, amr) (gnomAD).

What do computational predictors say about CCN3 p.Arg299His (c.896G>A)?

AlphaMissense predicts ambiguous (score 0.3833) — an in-silico prediction, not a clinical call.

CCN3 p.Arg299His

c.896G>A · rs142621486 · VCV3139803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3833 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.122%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3833	ambiguous
REVEL	0.65	pathogenic-leaning
SaProt	LLR -12.44	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 6,596 bp · p 0.65 · regional, not allelic
Overall
CADD	33.0	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 0.122% Admixed American · 73/59,990 alleles

Filtering AF 0.0992% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.091%

Overall 0.0273% 440/1,613,936 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.122%	822
South Asian	0.0604%	1,656
Remaining individualsnot grpmax-eligible	0.0288%	3,471
European (non-Finnish)	0.0246%	4,069
Finnishnot grpmax-eligible	0.00312%	32,016
East Asian	0.00223%	44,886
African / African-American	0.00134%	74,866

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.Arg299His
Coding: c.896G>A
MANE Select: NM_002514
dbSNP: rs142621486
Type: single nucleotide variant
Location: chr8:119422954 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88
Residue 299: a disulfide bond; the ctck domain

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

Similar variants

CCN3 p.Cys15Phe Benign ★★ same type
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.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-arg299his (accessed [today's date]).

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