Is CDK5RAP1 p.Ile415Phe (c.1243A>T) pathogenic?

CDK5RAP1 p.Ile415Phe (c.1243A>T) is classified Uncertain significance in CDK5RAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: ambiguous (0.5341); Absent from gnomAD v4.1.

How common is CDK5RAP1 p.Ile415Phe (c.1243A>T) in the general population?

CDK5RAP1 p.Ile415Phe (c.1243A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDK5RAP1 p.Ile415Phe (c.1243A>T)?

AlphaMissense predicts ambiguous (score 0.5341) — an in-silico prediction, not a clinical call.

CDK5RAP1 p.Ile415Phe

c.1243A>T · VCV4224600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5341 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5341	ambiguous
REVEL	0.753	pathogenic-leaning
SaProt	LLR -12.85	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.49, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 38 kb · p 0.004 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I429F vs ClinVar I415F) — verify the residue.

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: CDK5RAP1
Protein: p.Ile415Phe
Coding: c.1243A>T
MANE Select: NM_016408
Type: single nucleotide variant
Location: chr20:33372660 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.24
Residue 415: the radical sam core domain

Full CDK5RAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDK5RAP1 c.1107+5G>A Uncertain significance ★ same type
CDK5RAP1 p.Ala247Val Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Ala51Thr Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg130Gln Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg169Gln Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg169Trp Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg171Cys Uncertain significance ★ ⚠ same type
CDK5RAP1 p.Arg177Lys 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/cdk5rap1-p-ile415phe (accessed [today's date]).

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