Is CDKAL1 p.Pro401Ser (c.1201C>T) pathogenic?

CDKAL1 p.Pro401Ser (c.1201C>T) is classified Uncertain significance in CDKAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely pathogenic (0.5941); Ultra-rare (popmax 0.0126%, nfe).

How common is CDKAL1 p.Pro401Ser (c.1201C>T) in the general population?

CDKAL1 p.Pro401Ser (c.1201C>T) is ultra-rare (popmax 0.0126%, nfe) (gnomAD).

What do computational predictors say about CDKAL1 p.Pro401Ser (c.1201C>T)?

AlphaMissense predicts likely pathogenic (score 0.5941) — an in-silico prediction, not a clinical call.

CDKAL1 p.Pro401Ser

c.1201C>T · rs770105916 · VCV2309273

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5941 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0126%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5941	likely pathogenic
REVEL	0.528	indeterminate
SaProt	LLR -10.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 685 kb · p 0.00059 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0126% European (non-Finnish) · 149/1,178,518 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00963% 155/1,608,762 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0126%	7,910
Remaining individualsnot grpmax-eligible	0.00802%	12,467
African / African-American	0.00134%	74,644

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: CDKAL1
Protein: p.Pro401Ser
Coding: c.1201C>T
MANE Select: NM_017774
dbSNP: rs770105916
Type: single nucleotide variant
Location: chr6:21065193 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI 0.48 (gnomAD)
Structure: AlphaFold pLDDT 82.72
Residue 401: the radical sam core domain

Full CDKAL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKAL1 p.Arg39Gln Likely benign ★★ ⚠ same type
CDKAL1 p.Ala126Val Uncertain significance ★ ⚠ same type
CDKAL1 p.Ala316Thr Uncertain significance ★ ⚠ same type
CDKAL1 p.Ala325Pro Uncertain significance ★ ⚠ same type
CDKAL1 p.Ala495Gly Uncertain significance ★ ⚠ same type
CDKAL1 p.Ala507Thr Uncertain significance ★ ⚠ same type
CDKAL1 p.Ala534Thr Uncertain significance ★ ⚠ same type
CDKAL1 p.Ala535Thr 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/cdkal1-p-pro401ser (accessed [today's date]).

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