Is CCN6 p.His130Arg (c.389A>G) pathogenic?

CCN6 p.His130Arg (c.389A>G) is classified Uncertain significance in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.0538); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CCN6 p.His130Arg (c.389A>G)?

CCN6 p.His130Arg (c.389A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CCN6 p.His130Arg (c.389A>G) in the general population?

CCN6 p.His130Arg (c.389A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CCN6 p.His130Arg (c.389A>G)?

AlphaMissense predicts likely benign (score 0.0538) — an in-silico prediction, not a clinical call.

CCN6 p.His130Arg

c.389A>G · rs1312401479 · VCV3139844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0538	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -4.00	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 1.2	GERP -2.5, phastCons 0.01
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 0.028 · regional, not allelic
Overall
CADD	1.806	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,938 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,944 alleles · very rare

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: CCN6
Protein: p.His130Arg
Coding: c.389A>G
MANE Select: NM_198239
dbSNP: rs1312401479
Type: single nucleotide variant
Location: chr6:112064797 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 130: a UniProt-annotated variant site (in pprd)

Full CCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCN6 p.Cys337Tyr Pathogenic/Likely pathogenic ★★ same condition
CCN6 p.Ala15Thr Uncertain significance ★★ ⚠ same condition
CCN6 p.Asp253Asn Uncertain significance ★★ ⚠ same condition
CCN6 p.Gln133Glu Uncertain significance ★★ ⚠ same condition
CCN6 p.Gln289His Uncertain significance ★★ ⚠ same condition
CCN6 p.Glu123Lys Uncertain significance ★★ ⚠ same condition
CCN6 p.Lys173Glu Uncertain significance ★★ ⚠ same condition
CCN6 p.Lys206Glu Uncertain significance ★★ ⚠ same condition

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/ccn6-p-his130arg (accessed [today's date]).

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