Is CAMK2D p.Pro139Leu (c.416C>T) pathogenic?

CAMK2D p.Pro139Leu (c.416C>T) is classified Pathogenic in CAMK2D (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-03-07). AlphaMissense: likely pathogenic (0.9934); Absent from gnomAD v4.1; Associated with neurodevelopmental disorder.

What condition is associated with CAMK2D p.Pro139Leu (c.416C>T)?

CAMK2D p.Pro139Leu (c.416C>T) is associated with neurodevelopmental disorder (ClinVar).

How common is CAMK2D p.Pro139Leu (c.416C>T) in the general population?

CAMK2D p.Pro139Leu (c.416C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CAMK2D p.Pro139Leu (c.416C>T)?

AlphaMissense predicts likely pathogenic (score 0.9934) — an in-silico prediction, not a clinical call.

CAMK2D p.Pro139Leu

c.416C>T · rs2512545072 · VCV1343376

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9934 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9934	likely pathogenic ✓ concordant with ClinVar
REVEL	0.716	pathogenic-leaning
SaProt	LLR -12.98	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 15 kb · p 0.23 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CAMK2D
Protein: p.Pro139Leu
Coding: c.416C>T
MANE Select: NM_001321571
dbSNP: rs2512545072
Type: single nucleotide variant
Location: chr4:113537442 (GRCh38)
Gene constraint: LOEUF 0.447 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 84.10 · 9 PDB
Residue 139: the protein kinase domain; an α-helix

Full CAMK2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

CAMK2D p.Arg275His Pathogenic ★ same condition
CAMK2D p.Leu291Phe Pathogenic ★ same condition
CAMK2D p.Phe294Ser Likely pathogenic ★ same condition
CAMK2D p.Ser79Asn Likely pathogenic ★ same condition
CAMK2D c.275+1G>T Uncertain significance ★ same condition
CAMK2D p.Gln274Pro Pathogenic same condition
CAMK2D c.602-5T>C Benign ★★ same type
CAMK2D p.Asp167Glu Benign/Likely benign ★★ 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/camk2d-p-pro139leu (accessed [today's date]).

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