Is CCNF p.Ser158Leu (c.473C>T) pathogenic?

CCNF p.Ser158Leu (c.473C>T) is classified Uncertain significance in CCNF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: ambiguous (0.4965); Very rare (popmax 0.0033%, sas).

How common is CCNF p.Ser158Leu (c.473C>T) in the general population?

CCNF p.Ser158Leu (c.473C>T) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about CCNF p.Ser158Leu (c.473C>T)?

AlphaMissense predicts ambiguous (score 0.4965) — an in-silico prediction, not a clinical call.

CCNF p.Ser158Leu

c.473C>T · VCV4222096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Computational evidence

Protein change
AlphaMissense	0.4965	ambiguous
REVEL	0.357	indeterminate
SaProt	LLR -9.72	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0017 · regional, not allelic
Overall
CADD	25.5	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 0.0033% South Asian · 3/90,980 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000411% 6/1,459,000 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0033%	30,327
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,438
European (non-Finnish)	8.48e-05%	1,179,217

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.Ser158Leu
Coding: c.473C>T
MANE Select: NM_001761
Type: single nucleotide variant
Location: chr16:2437255 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 1 PDB

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-ser158leu (accessed [today's date]).

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