Is CCNL2 p.Arg447Trp (c.1339C>T) pathogenic?

CCNL2 p.Arg447Trp (c.1339C>T) is classified Uncertain significance in CCNL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-19). AlphaMissense: likely benign (0.0938); Ultra-rare (popmax 0.0223%, eas).

How common is CCNL2 p.Arg447Trp (c.1339C>T) in the general population?

CCNL2 p.Arg447Trp (c.1339C>T) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about CCNL2 p.Arg447Trp (c.1339C>T)?

AlphaMissense predicts likely benign (score 0.0938) — an in-silico prediction, not a clinical call.

CCNL2 p.Arg447Trp

c.1339C>T · rs772052659 · VCV2272187

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0938 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0938	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -8.74	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 5.4	GERP -2.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,554 bp · p 0.19 · regional, not allelic
Overall
CADD	27.1	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 0.0223% East Asian · 10/44,858 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00917%

Overall 0.00143% 23/1,613,184 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,486
Middle Eastern	0.0165%	6,078
Admixed American	0.00334%	29,974
African / African-American	0.00134%	74,822
South Asian	0.0011%	91,042
European (non-Finnish)	0.000678%	147,486

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: CCNL2
Protein: p.Arg447Trp
Coding: c.1339C>T
MANE Select: NM_030937
dbSNP: rs772052659
Type: single nucleotide variant
Location: chr1:1387455 (GRCh38)
Gene constraint: LOEUF 0.665 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.06 · 4 PDB
Residue 447: the 'disordered' region

Full CCNL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCNL2 p.Arg476Trp Uncertain significance ★★ ⚠ same type
CCNL2 p.Ala10Thr Uncertain significance ★ ⚠ same type
CCNL2 p.Ala18Thr Uncertain significance ★ ⚠ same type
CCNL2 p.Ala19Ser Uncertain significance ★ ⚠ same type
CCNL2 p.Ala22Ser Uncertain significance ★ ⚠ same type
CCNL2 p.Ala310Val Uncertain significance ★ ⚠ same type
CCNL2 p.Ala332Val Uncertain significance ★ ⚠ same type
CCNL2 p.Ala362Gly 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/ccnl2-p-arg447trp (accessed [today's date]).

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