Is CCN4 p.Val20Ile (c.58G>A) pathogenic?

CCN4 p.Val20Ile (c.58G>A) is classified Uncertain significance in CCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-23). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.0356%, mid).

How common is CCN4 p.Val20Ile (c.58G>A) in the general population?

CCN4 p.Val20Ile (c.58G>A) is ultra-rare (popmax 0.0356%, mid) (gnomAD).

What do computational predictors say about CCN4 p.Val20Ile (c.58G>A)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

CCN4 p.Val20Ile

c.58G>A · rs774136940 · VCV3139821

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.262	benign-leaning
SaProt	LLR -7.89	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 -2.1	GERP -3.5
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 1 · regional, not allelic
Overall
CADD	0.154	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 0.0356% Middle Eastern · 2/5,612 alleles

Filtering AF 0.00625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00697% 112/1,606,212 alleles · ultra-rare exomes 106/1,453,934 · genomes 6/152,278 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0356%	2,806
Finnishnot grpmax-eligible	0.0192%	5,216
Remaining individualsnot grpmax-eligible	0.0128%	7,794
Admixed American	0.00834%	11,992
European (non-Finnish)	0.00695%	14,386
African / African-American	0.004%	25,000
South Asian	0.0011%	90,894

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.Val20Ile
Coding: c.58G>A
MANE Select: NM_003882
dbSNP: rs774136940
Type: single nucleotide variant
Location: chr8:133191202 (GRCh38)
Gene constraint: LOEUF 1.151 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16

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-val20ile (accessed [today's date]).

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