Is CDKAL1 p.Leu271Phe (c.811C>T) pathogenic?

CDKAL1 p.Leu271Phe (c.811C>T) is classified Uncertain significance in CDKAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.6765); Very rare (popmax 0.000254%, nfe).

How common is CDKAL1 p.Leu271Phe (c.811C>T) in the general population?

CDKAL1 p.Leu271Phe (c.811C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CDKAL1 p.Leu271Phe (c.811C>T)?

AlphaMissense predicts likely pathogenic (score 0.6765) — an in-silico prediction, not a clinical call.

CDKAL1 p.Leu271Phe

c.811C>T · VCV4651582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6765	likely pathogenic
REVEL	0.238	benign-leaning
SaProt	LLR -12.17	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 685 kb · p 0.00059 · regional, not allelic
Overall
CADD	26.7	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 0.000254% European (non-Finnish) · 3/1,179,966 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,976 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: CDKAL1
Protein: p.Leu271Phe
Coding: c.811C>T
MANE Select: NM_017774
Type: single nucleotide variant
Location: chr6:20955487 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI 0.48 (gnomAD)
Structure: AlphaFold pLDDT 82.72
Residue 271: 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-leu271phe (accessed [today's date]).

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