Is CCN5 p.Pro193Thr (c.577C>A) pathogenic?

CCN5 p.Pro193Thr (c.577C>A) is classified Uncertain significance in CCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-30). AlphaMissense: likely benign (0.0769); Very rare (popmax 0.00815%, nfe).

How common is CCN5 p.Pro193Thr (c.577C>A) in the general population?

CCN5 p.Pro193Thr (c.577C>A) is very rare (popmax 0.00815%, nfe) (gnomAD).

What do computational predictors say about CCN5 p.Pro193Thr (c.577C>A)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

CCN5 p.Pro193Thr

c.577C>A · rs149467110 · VCV3139835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00815%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.24	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 0.43	GERP -2.6
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.19 · regional, not allelic
Overall
CADD	8.067	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 0.00815% European (non-Finnish) · 96/1,178,316 alleles

Filtering AF 0.00682% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00621% 100/1,610,918 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00815%	12,274
African / African-American	0.00267%	37,449
Admixed American	0.00167%	59,718
Remaining individualsnot grpmax-eligible	0.0016%	62,348

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: CCN5
Protein: p.Pro193Thr
Coding: c.577C>A
MANE Select: NM_003881
dbSNP: rs149467110
Type: single nucleotide variant
Location: chr20:44727131 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.59

Full CCN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCN5 p.Leu169= Benign ★★ same type
CCN5 p.Ala11Asp Uncertain significance ★ ⚠ same type
CCN5 p.Ala213Thr Uncertain significance ★ ⚠ same type
CCN5 p.Ala72Thr Uncertain significance ★ ⚠ same type
CCN5 p.Arg105Ser Uncertain significance ★ ⚠ same type
CCN5 p.Arg215Trp Uncertain significance ★ ⚠ same type
CCN5 p.Arg221His Uncertain significance ★ ⚠ same type
CCN5 p.Arg229Cys 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/ccn5-p-pro193thr (accessed [today's date]).

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