Is CCN5 p.Pro40Leu (c.119C>T) pathogenic?

CCN5 p.Pro40Leu (c.119C>T) is classified Uncertain significance in CCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely benign (0.1135); Ultra-rare (popmax 0.0117%, amr).

How common is CCN5 p.Pro40Leu (c.119C>T) in the general population?

CCN5 p.Pro40Leu (c.119C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about CCN5 p.Pro40Leu (c.119C>T)?

AlphaMissense predicts likely benign (score 0.1135) — an in-silico prediction, not a clinical call.

CCN5 p.Pro40Leu

c.119C>T · rs201427891 · VCV3139830

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1135 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1135	likely benign
REVEL	0.333	indeterminate
SaProt	LLR -11.36	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.19 · regional, not allelic
Overall
CADD	25.9	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 0.0117% Admixed American · 7/59,980 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00378% 61/1,613,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,569
African / African-American	0.00534%	18,734
East Asian	0.00446%	22,444
European (non-Finnish)	0.00398%	25,105
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Pro40Leu
Coding: c.119C>T
MANE Select: NM_003881
dbSNP: rs201427891
Type: single nucleotide variant
Location: chr20:44719955 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.59
Residue 40: the igfbp n-terminal domain; a disulfide bond

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-pro40leu (accessed [today's date]).

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