Is CMPK2 p.Pro159Leu (c.476C>T) pathogenic?

CMPK2 p.Pro159Leu (c.476C>T) is classified Likely benign in CMPK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.1152); Rare (popmax 0.124%, nfe); Associated with CMPK2-related disorder.

What condition is associated with CMPK2 p.Pro159Leu (c.476C>T)?

CMPK2 p.Pro159Leu (c.476C>T) is associated with CMPK2-related disorder (ClinVar).

How common is CMPK2 p.Pro159Leu (c.476C>T) in the general population?

CMPK2 p.Pro159Leu (c.476C>T) is rare (popmax 0.124%, nfe) (gnomAD).

What do computational predictors say about CMPK2 p.Pro159Leu (c.476C>T)?

AlphaMissense predicts likely benign (score 0.1152) — an in-silico prediction, not a clinical call.

CMPK2 p.Pro159Leu

c.476C>T · rs201663837 · VCV3046192

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1152 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.124%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CMPK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1152	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.17	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 -1.2, phastCons 0.89
Regional constraint	o/e 1.09	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	12.81	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 0.124% European (non-Finnish) · 1,425/1,146,694 alleles

Filtering AF 0.119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.117%

Overall 0.0957% 1,469/1,535,344 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.124%	805
Remaining individualsnot grpmax-eligible	0.0435%	2,299
Finnishnot grpmax-eligible	0.0145%	6,917
African / African-American	0.0142%	7,060
Admixed American	0.00193%	51,790

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: CMPK2
Protein: p.Pro159Leu
Coding: c.476C>T
MANE Select: NM_207315
dbSNP: rs201663837
Type: single nucleotide variant
Location: chr2:6865221 (GRCh38)
Gene constraint: LOEUF 1.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.26

Full CMPK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CMPK2-related disorder

Similar variants

CMPK2 p.Pro159Ser Uncertain significance ★ ⚠ same residue
CMPK2 p.Arg9Ser Uncertain significance ★ ⚠ same condition
CMPK2 p.His357Gln Uncertain significance ★ ⚠ same condition
CMPK2 p.Cys76Tyr Uncertain significance ⚠ same condition
CMPK2 p.Ala156Thr Uncertain significance ★ ⚠ same type
CMPK2 p.Ala24Gly Uncertain significance ★ ⚠ same type
CMPK2 p.Ala2Val Uncertain significance ★ ⚠ same type
CMPK2 p.Ala49Ser 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/cmpk2-p-pro159leu (accessed [today's date]).

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