Is CCN4 p.Val320Met (c.958G>A) pathogenic?

CCN4 p.Val320Met (c.958G>A) is classified Uncertain significance in CCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely benign (0.3053); Ultra-rare (popmax 0.0165%, mid).

How common is CCN4 p.Val320Met (c.958G>A) in the general population?

CCN4 p.Val320Met (c.958G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CCN4 p.Val320Met (c.958G>A)?

AlphaMissense predicts likely benign (score 0.3053) — an in-silico prediction, not a clinical call.

CCN4 p.Val320Met

c.958G>A · VCV3264501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3053 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3053	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.91, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 1 · regional, not allelic
Overall
CADD	16.63	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00229% 37/1,614,228 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.0134%	7,480
Remaining individualsnot grpmax-eligible	0.0064%	15,627
South Asian	0.00439%	22,771
European (non-Finnish)	0.00186%	53,639

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: CCN4
Protein: p.Val320Met
Coding: c.958G>A
MANE Select: NM_003882
Type: single nucleotide variant
Location: chr8:133227564 (GRCh38)
Gene constraint: LOEUF 1.151 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16
Residue 320: a disulfide bond; the ctck domain

Full CCN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN4 p.Arg97= Benign ★★ same type
CCN4 p.Leu99= Benign ★★ same type
CCN4 p.Thr145Met Likely benign ★★ ⚠ same type
CCN4 p.Ala10Glu Uncertain significance ★ ⚠ same type
CCN4 p.Ala10Thr Uncertain significance ★ ⚠ same type
CCN4 p.Ala17Ser Uncertain significance ★ ⚠ same type
CCN4 p.Ala196Thr Uncertain significance ★ ⚠ same type
CCN4 p.Ala243Ser 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/ccn4-p-val320met (accessed [today's date]).

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