Is CCN6 p.Ile157Val (c.469A>G) pathogenic?

CCN6 p.Ile157Val (c.469A>G) is classified Uncertain significance in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). AlphaMissense: likely benign (0.112); Very rare (popmax 0.00333%, amr).

How common is CCN6 p.Ile157Val (c.469A>G) in the general population?

CCN6 p.Ile157Val (c.469A>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CCN6 p.Ile157Val (c.469A>G)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

CCN6 p.Ile157Val

c.469A>G · rs587643325 · VCV1927687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.235	benign-leaning
SaProt	LLR -6.30	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 4.5	GERP 1.3, phastCons 0.98
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 0.028 · regional, not allelic
Overall
CADD	15.22	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 0.00333% Admixed American · 2/60,006 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,130 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.Ile157Val
Coding: c.469A>G
MANE Select: NM_198239
dbSNP: rs587643325
Type: single nucleotide variant
Location: chr6:112064877 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 157: a UniProt-annotated variant site (in pprd)

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

Similar variants

CCN6 c.49-1G>A Pathogenic/Likely pathogenic ★★ same type
CCN6 c.590-1G>C Likely pathogenic ★★ same type
CCN6 p.Ala197Pro Pathogenic/Likely pathogenic ★★ ⚠ same type
CCN6 p.Cys223Gly Pathogenic ★★ same type
CCN6 p.Cys337Tyr Pathogenic/Likely pathogenic ★★ same type
CCN6 p.Cys52Ter Pathogenic/Likely pathogenic ★★ same type
CCN6 p.Cys78Tyr Pathogenic/Likely pathogenic ★★ same type
CCN6 p.Met1Val Pathogenic/Likely pathogenic ★★ 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/ccn6-p-ile157val (accessed [today's date]).

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