Is CDK19 p.Arg464His (c.1391G>A) pathogenic?

CDK19 p.Arg464His (c.1391G>A) is classified Uncertain significance in CDK19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1035); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with CDK19 p.Arg464His (c.1391G>A)?

CDK19 p.Arg464His (c.1391G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDK19 p.Arg464His (c.1391G>A) in the general population?

CDK19 p.Arg464His (c.1391G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CDK19 p.Arg464His (c.1391G>A)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

CDK19 p.Arg464His

c.1391G>A · VCV4829266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -5.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.21 · evaluated, not missing
Pangolin	Δ0.20	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 8,332 bp · p 5.7e-06 · 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 0.00329% South Asian · 3/91,056 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000806% 13/1,613,546 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,352
East Asian	0.00223%	44,882
Admixed American	0.00167%	59,960
African / African-American	0.00134%	74,802
European (non-Finnish)	0.000593%	168,548

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: CDK19
Protein: p.Arg464His
Coding: c.1391G>A
MANE Select: NM_015076
Type: single nucleotide variant
Location: chr6:110614653 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 77.97
Residue 464: the 'disordered' region

Full CDK19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDK19 p.Arg464Cys Uncertain significance ★ ⚠ same residue
CDK19 p.Thr196Ala Pathogenic/Likely pathogenic ★★ same condition
CDK19 p.Lys47Asn Uncertain significance ★★ ⚠ same condition
CDK19 p.Pro495Thr Uncertain significance ★★ ⚠ same condition
CDK19 p.Arg112Cys Uncertain significance ★ ⚠ same condition
CDK19 p.Arg166Met Uncertain significance ★ ⚠ same condition
CDK19 p.Arg441Gln Uncertain significance ★ ⚠ same condition
CDK19 p.Arg501Gln Uncertain significance ★ ⚠ 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/cdk19-p-arg464his (accessed [today's date]).

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