Is CCN4 p.Arg129His (c.386G>A) pathogenic?

CCN4 p.Arg129His (c.386G>A) is classified Uncertain significance in CCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). AlphaMissense: likely benign (0.0688); Ultra-rare (popmax 0.0681%, sas).

How common is CCN4 p.Arg129His (c.386G>A) in the general population?

CCN4 p.Arg129His (c.386G>A) is ultra-rare (popmax 0.0681%, sas) (gnomAD).

What do computational predictors say about CCN4 p.Arg129His (c.386G>A)?

AlphaMissense predicts likely benign (score 0.0688) — an in-silico prediction, not a clinical call.

CCN4 p.Arg129His

c.386G>A · VCV3487323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0688 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0688	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -6.76	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 5.6	GERP -0.82, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 1 · regional, not allelic
Overall
CADD	22.4	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 0.0681% South Asian · 62/91,084 alleles

Filtering AF 0.0544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0495%

Overall 0.00607% 98/1,614,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0681%	1,469
Remaining individualsnot grpmax-eligible	0.0064%	15,627
Finnishnot grpmax-eligible	0.00469%	21,338
African / African-American	0.00266%	37,534
East Asian	0.00223%	44,872
European (non-Finnish)	0.0022%	45,384

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.Arg129His
Coding: c.386G>A
MANE Select: NM_003882
Type: single nucleotide variant
Location: chr8:133220617 (GRCh38)
Gene constraint: LOEUF 1.151 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16
Residue 129: the vwfc 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-arg129his (accessed [today's date]).

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