Is CCN4 p.Arg193Ser (c.577C>A) pathogenic?

CCN4 p.Arg193Ser (c.577C>A) is classified Uncertain significance in CCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely benign (0.2869); Ultra-rare (popmax 0.0201%, eas).

How common is CCN4 p.Arg193Ser (c.577C>A) in the general population?

CCN4 p.Arg193Ser (c.577C>A) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about CCN4 p.Arg193Ser (c.577C>A)?

AlphaMissense predicts likely benign (score 0.2869) — an in-silico prediction, not a clinical call.

CCN4 p.Arg193Ser

c.577C>A · rs756892752 · VCV2588515

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2869 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2869	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.35, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 1 · regional, not allelic
Overall
CADD	20.8	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 0.0201% East Asian · 9/44,700 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00782%

Overall 0.000995% 16/1,608,078 alleles · ultra-rare exomes 14/1,455,846 · genomes 2/152,232 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,967
Admixed American	0.00668%	14,980
Remaining individualsnot grpmax-eligible	0.00161%	62,096
European (non-Finnish)	0.00017%	588,408

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.Arg193Ser
Coding: c.577C>A
MANE Select: NM_003882
dbSNP: rs756892752
Type: single nucleotide variant
Location: chr8:133220808 (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.Arg193Leu 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-arg193ser (accessed [today's date]).

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