Is CDKL4 p.Leu171Pro (c.512T>C) pathogenic?

CDKL4 p.Leu171Pro (c.512T>C) is classified Uncertain significance in CDKL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-26). AlphaMissense: likely pathogenic (0.8551); Very rare (popmax 8.47e-05%, nfe).

How common is CDKL4 p.Leu171Pro (c.512T>C) in the general population?

CDKL4 p.Leu171Pro (c.512T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDKL4 p.Leu171Pro (c.512T>C)?

AlphaMissense predicts likely pathogenic (score 0.8551) — an in-silico prediction, not a clinical call.

CDKL4 p.Leu171Pro

c.512T>C · VCV3830948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8551 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8551	likely pathogenic · top 2% in CDKL4
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -13.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 54 kb · p 0.23 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.84e-05% 1/1,461,886 alleles · very rare

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: CDKL4
Protein: p.Leu171Pro
Coding: c.512T>C
MANE Select: NM_001397900
Type: single nucleotide variant
Location: chr2:39190445 (GRCh38)
Gene constraint: LOEUF 1.331 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.67
Residue 171: the protein kinase domain

Full CDKL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKL4 p.Ala168Pro Uncertain significance ★ ⚠ same type
CDKL4 p.Ala186Thr Uncertain significance ★ ⚠ same type
CDKL4 p.Arg167Gln Uncertain significance ★ ⚠ same type
CDKL4 p.Arg299Cys Uncertain significance ★ ⚠ same type
CDKL4 p.Asn62Ser Uncertain significance ★ ⚠ same type
CDKL4 p.Asn65Thr Uncertain significance ★ ⚠ same type
CDKL4 p.Asn94Lys Uncertain significance ★ ⚠ same type
CDKL4 p.Asp159Asn 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/cdkl4-p-leu171pro (accessed [today's date]).

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