Is CCN6 p.Trp50Arg (c.148T>C) pathogenic?

CCN6 p.Trp50Arg (c.148T>C) is classified Likely benign in CCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.744); Rare (popmax 0.188%, afr).

How common is CCN6 p.Trp50Arg (c.148T>C) in the general population?

CCN6 p.Trp50Arg (c.148T>C) is rare (popmax 0.188%, afr) (gnomAD).

What do computational predictors say about CCN6 p.Trp50Arg (c.148T>C)?

AlphaMissense predicts likely pathogenic (score 0.744) — an in-silico prediction, not a clinical call.

CCN6 p.Trp50Arg

c.148T>C · rs35914692 · VCV1680457

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.744 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.188%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.744	likely pathogenic
REVEL	0.46	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 15 kb · p 0.028 · regional, not allelic
Overall
CADD	25.9	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 0.188% African / African-American · 141/75,052 alleles

Filtering AF 0.163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.153%

Overall 0.00973% 157/1,614,198 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.188%	532
Remaining individualsnot grpmax-eligible	0.0128%	7,814
Admixed American	0.0117%	8,574
European (non-Finnish)	8.47e-05%	1,180,020

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.Trp50Arg
Coding: c.148T>C
MANE Select: NM_198239
dbSNP: rs35914692
Type: single nucleotide variant
Location: chr6:112061090 (GRCh38)
Gene constraint: LOEUF 1.055 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 74.30
Residue 50: a UniProt-annotated variant site (in pprd); the igfbp n-terminal domain; a disulfide bond

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

Similar variants

CCN6 p.Trp50Ter Pathogenic ★★ same residue
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

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-trp50arg (accessed [today's date]).

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