Is CCNK p.Val246Ile (c.736G>A) pathogenic?

CCNK p.Val246Ile (c.736G>A) is classified Uncertain significance in CCNK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-21). AlphaMissense: likely benign (0.1337); Ultra-rare (popmax 0.0446%, eas); Associated with intellectual developmental disorder with hypertelorism and distinctive facies.

How common is CCNK p.Val246Ile (c.736G>A) in the general population?

CCNK p.Val246Ile (c.736G>A) is ultra-rare (popmax 0.0446%, eas) (gnomAD).

What do computational predictors say about CCNK p.Val246Ile (c.736G>A)?

AlphaMissense predicts likely benign (score 0.1337) — an in-silico prediction, not a clinical call.

CCNK p.Val246Ile

Q: What condition is associated with CCNK p.Val246Ile (c.736G>A)?

CCNK p.Val246Ile (c.736G>A) is associated with intellectual developmental disorder with hypertelorism and distinctive facies (ClinVar).

c.736G>A · rs750789680 · VCV996902

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1337 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with hypertelorism and distinctive facies

Computational evidence

Protein change
AlphaMissense	0.1337	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -4.38	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 9.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 1,995 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	21.7	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 0.0446% East Asian · 20/44,878 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00297% 48/1,613,468 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,244
European (non-Finnish)	0.0022%	45,375
Admixed American	0.00167%	59,958
African / African-American	0.00134%	74,886

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: CCNK
Protein: p.Val246Ile
Coding: c.736G>A
MANE Select: NM_001099402
dbSNP: rs750789680
Type: single nucleotide variant
Location: chr14:99502367 (GRCh38)
Gene constraint: LOEUF 0.34 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.43 · 43 PDB
Residue 246: an α-helix

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

Disease context

intellectual developmental disorder with hypertelorism and distinctive facies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CCNK p.Arg80Cys Uncertain significance ★★ ⚠ same condition
CCNK c.280-5T>C Benign ★★ same condition
CCNK p.Lys111Glu Likely pathogenic ★ same condition
CCNK p.Met1Val Uncertain significance ★ same condition
CCNK p.Glu46fs Uncertain significance ★ same condition
CCNK p.Arg48Gln Uncertain significance ★★ ⚠ same type
CCNK p.Ser11= Likely benign ★★ same type
CCNK p.Ala54Thr 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/ccnk-p-val246ile (accessed [today's date]).

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