Is CMPK2 p.Cys76Tyr (c.227G>A) pathogenic?

CMPK2 p.Cys76Tyr (c.227G>A) is classified Uncertain significance in CMPK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-06-08). AlphaMissense: ambiguous (0.3581); Very rare (popmax 0.00647%, eas); Associated with CMPK2-related disorder.

What condition is associated with CMPK2 p.Cys76Tyr (c.227G>A)?

CMPK2 p.Cys76Tyr (c.227G>A) is associated with CMPK2-related disorder (ClinVar).

How common is CMPK2 p.Cys76Tyr (c.227G>A) in the general population?

CMPK2 p.Cys76Tyr (c.227G>A) is very rare (popmax 0.00647%, eas) (gnomAD).

What do computational predictors say about CMPK2 p.Cys76Tyr (c.227G>A)?

AlphaMissense predicts ambiguous (score 0.3581) — an in-silico prediction, not a clinical call.

CMPK2 p.Cys76Tyr

c.227G>A · VCV3348442

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3581 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00647%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CMPK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.3581	ambiguous
REVEL	0.117	moderately benign-leaning
SaProt	LLR -5.85	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 16 kb · p 0.024 · regional, not allelic
Overall
CADD	21.1	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 0.00647% East Asian · 2/30,896 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000401%

Overall 0.000178% 2/1,125,138 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: CMPK2
Protein: p.Cys76Tyr
Coding: c.227G>A
MANE Select: NM_207315
Type: single nucleotide variant
Location: chr2:6865470 (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.Arg9Ser Uncertain significance ★ ⚠ same condition
CMPK2 p.His357Gln Uncertain significance ★ ⚠ same condition
CMPK2 p.Pro159Leu Likely benign 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
CMPK2 p.Ala49Thr 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-cys76tyr (accessed [today's date]).

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