Is CCN3 p.Thr7Met (c.20C>T) pathogenic?

CCN3 p.Thr7Met (c.20C>T) is classified Likely benign in CCN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-26). AlphaMissense: likely benign (0.0892); Ultra-rare (popmax 0.0535%, eas).

How common is CCN3 p.Thr7Met (c.20C>T) in the general population?

CCN3 p.Thr7Met (c.20C>T) is ultra-rare (popmax 0.0535%, eas) (gnomAD).

What do computational predictors say about CCN3 p.Thr7Met (c.20C>T)?

AlphaMissense predicts likely benign (score 0.0892) — an in-silico prediction, not a clinical call.

CCN3 p.Thr7Met

c.20C>T · rs201275451 · VCV3139798

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0892 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0892	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -7.11	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 -0.58	GERP -4.4
Regional constraint	o/e 1.02	unconstrained · MANE · 6,596 bp · p 0.65 · regional, not allelic
Overall
CADD	6.539	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 0.0535% East Asian · 24/44,884 alleles

Filtering AF 0.0368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0313%

Overall 0.00415% 67/1,613,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0576%	1,736
East Asiangrpmax	0.0535%	1,870
African / African-American	0.00667%	14,987
Admixed American	0.00167%	59,974
South Asian	0.0011%	90,972

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr7Met
Coding: c.20C>T
MANE Select: NM_002514
dbSNP: rs201275451
Type: single nucleotide variant
Location: chr8:119416552 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88

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

Similar variants

CCN3 p.Thr7Lys Uncertain significance ★ ⚠ same residue
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

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-thr7met (accessed [today's date]).

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