Is CCN4 p.Arg172His (c.515G>A) pathogenic?

CCN4 p.Arg172His (c.515G>A) is classified Uncertain significance in CCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.0882); Very rare (popmax 0.00932%, afr).

How common is CCN4 p.Arg172His (c.515G>A) in the general population?

CCN4 p.Arg172His (c.515G>A) is very rare (popmax 0.00932%, afr) (gnomAD).

What do computational predictors say about CCN4 p.Arg172His (c.515G>A)?

AlphaMissense predicts likely benign (score 0.0882) — an in-silico prediction, not a clinical call.

CCN4 p.Arg172His

c.515G>A · rs983447505 · VCV3139815

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00932%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0882	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -10.45	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 1.6	GERP -3.8, phastCons 0.005
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 1 · regional, not allelic
Overall
CADD	15.63	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 0.00932% African / African-American · 7/75,070 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00219% 32/1,461,158 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00932%	10,724
Admixed American	0.00333%	30,008
European (non-Finnish)	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Arg172His
Coding: c.515G>A
MANE Select: NM_003882
dbSNP: rs983447505
Type: single nucleotide variant
Location: chr8:133220746 (GRCh38)
Gene constraint: LOEUF 1.151 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16
Residue 172: the vwfc domain

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

Similar variants

CCN4 p.Arg172Ser 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-arg172his (accessed [today's date]).

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