Is CDK15 p.Ala378Thr (c.1132G>A) pathogenic?

CDK15 p.Ala378Thr (c.1132G>A) is classified Uncertain significance in CDK15 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-20). AlphaMissense: ambiguous (0.3557); Ultra-rare (popmax 0.0134%, afr).

How common is CDK15 p.Ala378Thr (c.1132G>A) in the general population?

CDK15 p.Ala378Thr (c.1132G>A) is ultra-rare (popmax 0.0134%, afr) (gnomAD).

What do computational predictors say about CDK15 p.Ala378Thr (c.1132G>A)?

AlphaMissense predicts ambiguous (score 0.3557) — an in-silico prediction, not a clinical call.

CDK15 p.Ala378Thr

c.1132G>A · VCV3265435

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3557 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, afr)

Computational evidence

Protein change
AlphaMissense	0.3557	ambiguous
REVEL	0.604	indeterminate
SaProt	LLR -10.21	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 84 kb · p 0.56 · regional, not allelic
Overall
CADD	29.1	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 0.0134% African / African-American · 10/74,894 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00266% 43/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0134%	7,489
South Asian	0.00329%	30,361
European (non-Finnish)	0.00237%	42,143
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: CDK15
Protein: p.Ala378Thr
Coding: c.1132G>A
MANE Select: NM_001366386
Type: single nucleotide variant
Location: chr2:201880101 (GRCh38)
Gene constraint: LOEUF 1.291 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.75
Residue 378: the protein kinase domain

Full CDK15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK15 p.Ala115Val Uncertain significance ★ ⚠ same type
CDK15 p.Ala63Ser Uncertain significance ★ ⚠ same type
CDK15 p.Arg148Gln Uncertain significance ★ ⚠ same type
CDK15 p.Arg247Gln Uncertain significance ★ ⚠ same type
CDK15 p.Arg266Trp Uncertain significance ★ ⚠ same type
CDK15 p.Arg74Gln Uncertain significance ★ ⚠ same type
CDK15 p.Asn105Tyr Uncertain significance ★ ⚠ same type
CDK15 p.Asn200Thr 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/cdk15-p-ala378thr (accessed [today's date]).

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