Is CCN5 p.Arg221His (c.662G>A) pathogenic?

CCN5 p.Arg221His (c.662G>A) is classified Uncertain significance in CCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely benign (0.0888); Very rare (popmax 0.00517%, nfe).

How common is CCN5 p.Arg221His (c.662G>A) in the general population?

CCN5 p.Arg221His (c.662G>A) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about CCN5 p.Arg221His (c.662G>A)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

CCN5 p.Arg221His

c.662G>A · VCV3487334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -9.15	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 -0.67	GERP -3.6
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.19 · regional, not allelic
Overall
CADD	14.04	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 0.00517% European (non-Finnish) · 61/1,180,008 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00459% 74/1,613,440 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,618
European (non-Finnish)grpmax	0.00517%	19,344
East Asian	0.00446%	22,443
African / African-American	0.004%	24,973
South Asian	0.00329%	30,357
Admixed American	0.00167%	59,990

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg221His
Coding: c.662G>A
MANE Select: NM_003881
Type: single nucleotide variant
Location: chr20:44727216 (GRCh38)
Gene constraint: LOEUF 1.47 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.59
Residue 221: the tsp type-1 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.Ala72Thr Uncertain significance ★ ⚠ same type
CCN5 p.Arg105Ser Uncertain significance ★ ⚠ same type
CCN5 p.Arg215Trp 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-arg221his (accessed [today's date]).

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