Is CCNL2 p.Arg506His (c.1517G>A) pathogenic?

CCNL2 p.Arg506His (c.1517G>A) is classified Likely benign in CCNL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.0578); Ultra-rare (popmax 0.0774%, afr).

How common is CCNL2 p.Arg506His (c.1517G>A) in the general population?

CCNL2 p.Arg506His (c.1517G>A) is ultra-rare (popmax 0.0774%, afr) (gnomAD).

What do computational predictors say about CCNL2 p.Arg506His (c.1517G>A)?

AlphaMissense predicts likely benign (score 0.0578) — an in-silico prediction, not a clinical call.

CCNL2 p.Arg506His

c.1517G>A · rs374382413 · VCV2366113

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0578 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0774%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0578	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -7.90	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 0.91	GERP -1.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,554 bp · p 0.19 · regional, not allelic
Overall
CADD	11.68	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 0.0774% African / African-American · 58/74,950 alleles

Filtering AF 0.0614% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0557%

Overall 0.00459% 74/1,611,994 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0774%	1,292
Middle Eastern	0.0164%	6,080
East Asian	0.0156%	6,415
Admixed American	0.00667%	15,002
European (non-Finnish)	0.000339%	295,001

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.Arg506His
Coding: c.1517G>A
MANE Select: NM_030937
dbSNP: rs374382413
Type: single nucleotide variant
Location: chr1:1387277 (GRCh38)
Gene constraint: LOEUF 0.665 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.06 · 4 PDB
Residue 506: 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-arg506his (accessed [today's date]).

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