Is CCNL2 p.Arg474Trp (c.1420C>T) pathogenic?

CCNL2 p.Arg474Trp (c.1420C>T) is classified Uncertain significance in CCNL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.1483); Ultra-rare (popmax 0.0329%, mid).

How common is CCNL2 p.Arg474Trp (c.1420C>T) in the general population?

CCNL2 p.Arg474Trp (c.1420C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CCNL2 p.Arg474Trp (c.1420C>T)?

AlphaMissense predicts likely benign (score 0.1483) — an in-silico prediction, not a clinical call.

CCNL2 p.Arg474Trp

c.1420C>T · rs200276576 · VCV2508563

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1483 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1483	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -8.63	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 3.5	GERP -0.82, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,554 bp · p 0.19 · regional, not allelic
Overall
CADD	26.0	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00514% 83/1,614,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.149%	673
Middle Easterngrpmax	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.0096%	10,414
South Asian	0.00549%	18,218
East Asian	0.00223%	44,898
European (non-Finnish)	0.00195%	51,307
Admixed American	0.00167%	60,004
Finnishnot grpmax-eligible	0.00156%	63,984

Ashkenazi Jewish 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: CCNL2
Protein: p.Arg474Trp
Coding: c.1420C>T
MANE Select: NM_030937
dbSNP: rs200276576
Type: single nucleotide variant
Location: chr1:1387374 (GRCh38)
Gene constraint: LOEUF 0.665 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.06 · 4 PDB
Residue 474: the 'disordered' region

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

Similar variants

CCNL2 p.Arg474Gln Uncertain significance ★ ⚠ same residue
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

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-arg474trp (accessed [today's date]).

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