Is CCN5 p.Ala72Thr (c.214G>A) pathogenic?

CCN5 p.Ala72Thr (c.214G>A) is classified Uncertain significance in CCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). AlphaMissense: likely benign (0.0702); Ultra-rare (popmax 0.0135%, eas).

How common is CCN5 p.Ala72Thr (c.214G>A) in the general population?

CCN5 p.Ala72Thr (c.214G>A) is ultra-rare (popmax 0.0135%, eas) (gnomAD).

What do computational predictors say about CCN5 p.Ala72Thr (c.214G>A)?

AlphaMissense predicts likely benign (score 0.0702) — an in-silico prediction, not a clinical call.

CCN5 p.Ala72Thr

c.214G>A · VCV3829043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0702	likely benign
REVEL	0.039	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 -3.1	GERP -3.9
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.19 · regional, not allelic
Overall
CADD	0.034	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 0.0135% East Asian · 6/44,332 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00398%

Overall 0.00189% 30/1,590,582 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0135%	7,389
European (non-Finnish)	0.00196%	51,032
Remaining individualsnot grpmax-eligible	0.00162%	61,778

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.Ala72Thr
Coding: c.214G>A
MANE Select: NM_003881
Type: single nucleotide variant
Location: chr20:44720050 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.59
Residue 72: a disulfide bond; the igfbp n-terminal domain

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.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
CCN5 p.Arg22His 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-ala72thr (accessed [today's date]).

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