Is CDKL5 p.Arg981Ter (c.2941C>T) pathogenic?

CDKL5 p.Arg981Ter (c.2941C>T) is classified Likely benign in CDKL5 (ClinVar, Expert panel, 5 submitters; last evaluated 2023-12-06). Very rare (popmax 0.00351%, sas); Associated with CDKL5 disorder.

What condition is associated with CDKL5 p.Arg981Ter (c.2941C>T)?

CDKL5 p.Arg981Ter (c.2941C>T) is associated with CDKL5 disorder, developmental and epileptic encephalopathy, 2 (ClinVar).

How common is CDKL5 p.Arg981Ter (c.2941C>T) in the general population?

CDKL5 p.Arg981Ter (c.2941C>T) is very rare (popmax 0.00351%, sas) (gnomAD).

CDKL5 p.Arg981Ter

c.2941C>T · rs374054249 · VCV930627

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00351%, sas)

Conditions

CDKL5 disorder

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for CDKL5 disorder. Applied ACMG criteria (verbatim):

BS2

Curation rationale (ClinGen, verbatim)

RS1(NM_000330.4) and an alternative transcript of CDKL5 (NM_003159.2) are overlapping transcripts; however, these variants are in the noncoding 3' region of the main CDKL5 transcript (NM_001323289.2). The c.2941C>T (p.Arg981Ter) variant in CDKL5 transcript (NM_003159.2) (RS1 c.185-3221G>A) is present in 14 XX and 7 XY individuals in gnomAD v4 (0.0043%) (not sufficient to meet BS1 criteria). The p.Arg981Ter variant in CDKL5 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. While loss-of-function variants are commonly observed in affected individuals in this gene, there is a paucity of these variants in this region of the gene to date (not sufficient to meet PVS1 criteria). Additionally, the p.Arg981Ter variant is observed in at least 6 unaffected individuals (internal database - Invitae, internal database - GeneDx) (BS2). In the absence of conflicting evidence, this is sufficient evidence to classify as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel. In summary, the p.Arg981Ter variant in CDKL5 (NM_003159.2) is classified as likely benign based on the ACMG/AMP criteria (BS2).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -2
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00351% South Asian · 2/57,035 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000856%

Overall 0.00191% 21/1,098,155 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0042%	23,830
South Asiangrpmax	0.00351%	28,517
European (non-Finnish)	0.00179%	55,973
African / African-American	0.00173%	57,923

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: CDKL5
Protein: p.Arg981Ter
Coding: c.2941C>T
MANE Select: NM_001323289 · reported on NM_003159
dbSNP: rs374054249
Type: single nucleotide variant
Location: chrX:18650553 (GRCh38)
Structure: AlphaFold pLDDT 53.76 · 3 PDB

Full CDKL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CDKL5 disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 2

Similar variants

CDKL5 p.Arg981Gly Benign ★★★ same residue
CDKL5 c.146-1G>A Pathogenic ★★★ same condition
CDKL5 p.Ala157Pro Likely pathogenic ★★★ same condition
CDKL5 p.Ala157Val Likely pathogenic ★★★ same condition
CDKL5 p.Ala40Val Pathogenic ★★★ same condition
CDKL5 p.Arg178Gln Pathogenic ★★★ same condition
CDKL5 p.Arg717= Likely pathogenic ★★★ same condition
CDKL5 p.Arg948Ter Pathogenic ★★★ 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/cdkl5-p-arg981ter (accessed [today's date]).

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