Is CCN6 p.Leu185Pro (c.554T>C) pathogenic?

CCN6 p.Leu185Pro (c.554T>C) is classified Uncertain significance in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: likely benign (0.0523); Absent from gnomAD v4.1.

How common is CCN6 p.Leu185Pro (c.554T>C) in the general population?

CCN6 p.Leu185Pro (c.554T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCN6 p.Leu185Pro (c.554T>C)?

AlphaMissense predicts likely benign (score 0.0523) — an in-silico prediction, not a clinical call.

CCN6 p.Leu185Pro

c.554T>C · VCV3699834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0523 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0523	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -6.61	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	GERP -4.8, phastCons 0.004
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 0.028 · regional, not allelic
Overall
CADD	10.28	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

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: CCN6
Protein: p.Leu185Pro
Coding: c.554T>C
MANE Select: NM_198239
Type: single nucleotide variant
Location: chr6:112064962 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 185: 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-leu185pro (accessed [today's date]).

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