Is CCNK p.Val333Phe (c.997G>T) pathogenic?

CCNK p.Val333Phe (c.997G>T) is classified Uncertain significance in CCNK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-17). AlphaMissense: likely benign (0.1169); Ultra-rare (popmax 0.0178%, nfe); Associated with intellectual developmental disorder with hypertelorism and distinctive facies.

How common is CCNK p.Val333Phe (c.997G>T) in the general population?

CCNK p.Val333Phe (c.997G>T) is ultra-rare (popmax 0.0178%, nfe) (gnomAD).

What do computational predictors say about CCNK p.Val333Phe (c.997G>T)?

AlphaMissense predicts likely benign (score 0.1169) — an in-silico prediction, not a clinical call.

CCNK p.Val333Phe

Q: What condition is associated with CCNK p.Val333Phe (c.997G>T)?

CCNK p.Val333Phe (c.997G>T) is associated with intellectual developmental disorder with hypertelorism and distinctive facies (ClinVar).

c.997G>T · VCV3264574

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1169 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with hypertelorism and distinctive facies

Computational evidence

Protein change
AlphaMissense	0.1169	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -9.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4.5	GERP 0.66, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 7,692 bp · p 0.0051 · regional, not allelic
Overall
CADD	21.3	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 0.0178% European (non-Finnish) · 210/1,179,912 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0135% 218/1,613,876 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0178%	5,619
Remaining individualsnot grpmax-eligible	0.0064%	15,617
Admixed American	0.005%	20,003
African / African-American	0.00133%	74,912

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.Val333Phe
Coding: c.997G>T
MANE Select: NM_001144995 · reported on NM_001099402
Type: single nucleotide variant
Location: chr14:99502970 (GRCh38)

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

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-val333phe (accessed [today's date]).

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