Is CDK12 p.Leu347Phe (c.1039C>T) pathogenic?

CDK12 p.Leu347Phe (c.1039C>T) is classified Uncertain significance in CDK12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-23). AlphaMissense: likely benign (0.0797); Very rare (popmax 8.48e-05%, nfe).

How common is CDK12 p.Leu347Phe (c.1039C>T) in the general population?

CDK12 p.Leu347Phe (c.1039C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CDK12 p.Leu347Phe (c.1039C>T)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

CDK12 p.Leu347Phe

c.1039C>T · VCV3830555

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -7.11	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 3.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 8,924 bp · p 0.17 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.48e-05% European (non-Finnish) · 1/1,179,748 alleles

Overall 6.84e-05% 1/1,461,342 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: CDK12
Protein: p.Leu347Phe
Coding: c.1039C>T
MANE Select: NM_016507
Type: single nucleotide variant
Location: chr17:39463110 (GRCh38)
Gene constraint: LOEUF 0.21 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 51.39 · 39 PDB
Residue 347: the 'disordered' region

Full CDK12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK12 p.Leu347Pro Uncertain significance ★ ⚠ same residue
CDK12 p.Leu347Val Uncertain significance ★ ⚠ same residue
CDK12 p.Leu347= Likely benign ★ same residue
CDK12 c.2108+56T>A Benign/Likely benign ★★ same type
CDK12 c.2666+17A>C Benign ★★ same type
CDK12 c.2769-74G>A Benign ★★ same type
CDK12 c.2846+157G>T Benign ★★ same type
CDK12 c.2963+111T>A 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/cdk12-p-leu347phe (accessed [today's date]).

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