Is CDKAL1 p.Val562Met (c.1684G>A) pathogenic?

CDKAL1 p.Val562Met (c.1684G>A) is classified Uncertain significance in CDKAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-28). AlphaMissense: likely benign (0.1205); Very rare (popmax 0.00666%, afr).

How common is CDKAL1 p.Val562Met (c.1684G>A) in the general population?

CDKAL1 p.Val562Met (c.1684G>A) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about CDKAL1 p.Val562Met (c.1684G>A)?

AlphaMissense predicts likely benign (score 0.1205) — an in-silico prediction, not a clinical call.

CDKAL1 p.Val562Met

c.1684G>A · rs769795415 · VCV2408976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1205	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -8.07	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 1.5	GERP 2.3, phastCons 0.002
Regional constraint	o/e 0.87	unconstrained · MANE · 685 kb · p 0.00059 · regional, not allelic
Overall
CADD	19.32	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 0.00666% African / African-American · 5/75,044 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.0018% 29/1,613,130 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00666%	15,009
East Asian	0.00446%	22,428
Admixed American	0.00333%	30,001
South Asian	0.0033%	30,305
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)	0.00136%	73,705

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.Val562Met
Coding: c.1684G>A
MANE Select: NM_017774
dbSNP: rs769795415
Type: single nucleotide variant
Location: chr6:21230983 (GRCh38)
Gene constraint: LOEUF 0.643 · pLI 0.48 (gnomAD)
Structure: AlphaFold pLDDT 82.72

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-val562met (accessed [today's date]).

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