Is CCNF p.Ser566Leu (c.1697C>T) pathogenic?

CCNF p.Ser566Leu (c.1697C>T) is classified Uncertain significance in CCNF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-25). AlphaMissense: likely benign (0.1199); Ultra-rare (popmax 0.012%, afr).

How common is CCNF p.Ser566Leu (c.1697C>T) in the general population?

CCNF p.Ser566Leu (c.1697C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about CCNF p.Ser566Leu (c.1697C>T)?

AlphaMissense predicts likely benign (score 0.1199) — an in-silico prediction, not a clinical call.

CCNF p.Ser566Leu

c.1697C>T · VCV3487417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1199 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1199	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -6.83	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 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 8,082 bp · p 0.66 · regional, not allelic
Overall
CADD	26.0	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 0.012% African / African-American · 9/74,928 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.00186% 30/1,613,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,325
Remaining individualsnot grpmax-eligible	0.0032%	31,239
East Asian	0.00223%	44,896
Admixed American	0.00167%	60,004
European (non-Finnish)	0.00136%	73,752
South Asian	0.0011%	91,092

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: CCNF
Protein: p.Ser566Leu
Coding: c.1697C>T
MANE Select: NM_001761
Type: single nucleotide variant
Location: chr16:2453519 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 1 PDB
Residue 566: the 'disordered' region

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

Similar variants

CCNF p.Ser621Gly Pathogenic/Likely pathogenic ★★ ⚠ same type
CCNF p.Arg140Gln Uncertain significance ★★ ⚠ same type
CCNF p.Arg24Lys Uncertain significance ★★ ⚠ same type
CCNF p.Arg572Gln Uncertain significance ★★ ⚠ same type
CCNF p.Gly254Ala Uncertain significance ★★ ⚠ same type
CCNF p.Gly719Val Uncertain significance ★★ ⚠ same type
CCNF c.1095-28A>G Benign ★★ same type
CCNF c.1095-7G>A Benign ★★ 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/ccnf-p-ser566leu (accessed [today's date]).

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