Is CCNL2 p.Ser25Cys (c.74C>G) pathogenic?

CCNL2 p.Ser25Cys (c.74C>G) is classified Likely benign in CCNL2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2023-03-07). AlphaMissense: likely benign (0.1114); Rare (popmax 0.433%, eas); Associated with CCNL2-related disorder.

What condition is associated with CCNL2 p.Ser25Cys (c.74C>G)?

CCNL2 p.Ser25Cys (c.74C>G) is associated with CCNL2-related disorder (ClinVar).

How common is CCNL2 p.Ser25Cys (c.74C>G) in the general population?

CCNL2 p.Ser25Cys (c.74C>G) is rare (popmax 0.433%, eas) (gnomAD).

What do computational predictors say about CCNL2 p.Ser25Cys (c.74C>G)?

AlphaMissense predicts likely benign (score 0.1114) — an in-silico prediction, not a clinical call.

CCNL2 p.Ser25Cys

c.74C>G · rs376963263 · VCV3052965

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1114 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.433%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CCNL2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1114	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -9.56	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 -2.8, phastCons 0.99
Regional constraint	o/e 1.06	unconstrained · MANE · 3,876 bp · p 0.35 · regional, not allelic
Overall
CADD	20.9	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 0.433% East Asian · 184/42,508 alleles

Filtering AF 0.382% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.362%

Overall 0.0204% 325/1,594,564 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.433%	231
Remaining individualsnot grpmax-eligible	0.177%	564
Admixed American	0.0341%	2,932
African / African-American	0.00692%	14,441
South Asian	0.00112%	89,218
European (non-Finnish)	0.000512%	195,406

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.Ser25Cys
Coding: c.74C>G
MANE Select: NM_030937
dbSNP: rs376963263
Type: single nucleotide variant
Location: chr1:1399233 (GRCh38)
Gene constraint: LOEUF 0.665 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.06 · 4 PDB

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

Disease context

CCNL2-related disorder

Similar variants

CCNL2 p.Ser25Phe Uncertain significance ★ ⚠ same residue
CCNL2 c.*4G>A Benign same condition
CCNL2 p.Arg40= Likely benign same condition
CCNL2 p.Ser327= Likely benign same condition
CCNL2 p.Ser330= Likely benign same condition
CCNL2 p.Ser67= Likely benign same condition
CCNL2 c.473+10_473+13del Likely benign same condition
CCNL2 c.474-6del Likely benign same condition

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-ser25cys (accessed [today's date]).

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