Is CCN4 p.Ile112Arg (c.335T>G) pathogenic?

CCN4 p.Ile112Arg (c.335T>G) is classified Uncertain significance in CCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-07). AlphaMissense: likely benign (0.1675); Very rare (popmax 0.000512%, nfe).

How common is CCN4 p.Ile112Arg (c.335T>G) in the general population?

CCN4 p.Ile112Arg (c.335T>G) is very rare (popmax 0.000512%, nfe) (gnomAD).

What do computational predictors say about CCN4 p.Ile112Arg (c.335T>G)?

AlphaMissense predicts likely benign (score 0.1675) — an in-silico prediction, not a clinical call.

CCN4 p.Ile112Arg

c.335T>G · rs1317326427 · VCV3139808

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1675 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000512%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1675	likely benign
REVEL	0.212	benign-leaning
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.37	donor gain, 14 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 6.1	GERP -0.15, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 1 · regional, not allelic
Overall
CADD	23.8	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 0.000512% European (non-Finnish) · 6/1,170,896 alleles

Filtering AF 0.000184% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000412% 6/1,455,142 alleles · very rare

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.Ile112Arg
Coding: c.335T>G
MANE Select: NM_003882
dbSNP: rs1317326427
Type: single nucleotide variant
Location: chr8:133213129 (GRCh38)
Gene constraint: LOEUF 1.151 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16
Residue 112: a disulfide bond; the igfbp n-terminal domain

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

Similar variants

CCN4 p.Ile112Thr Uncertain significance ★ ⚠ same residue
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

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-ile112arg (accessed [today's date]).

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