Is CCNF p.Arg392Thr (c.1175G>C) pathogenic?

CCNF p.Arg392Thr (c.1175G>C) is classified Pathogenic in CCNF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-01-06). AlphaMissense: likely pathogenic (0.8851); Very rare (popmax 0.000254%, nfe); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 5.

What condition is associated with CCNF p.Arg392Thr (c.1175G>C)?

CCNF p.Arg392Thr (c.1175G>C) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 5 (ClinVar).

How common is CCNF p.Arg392Thr (c.1175G>C) in the general population?

CCNF p.Arg392Thr (c.1175G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CCNF p.Arg392Thr (c.1175G>C)?

AlphaMissense predicts likely pathogenic (score 0.8851) — an in-silico prediction, not a clinical call.

CCNF p.Arg392Thr

Q: How is Frontotemporal dementia with motor neuron disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1175G>C · rs954539468 · VCV992593

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 5

Computational evidence

Protein change
AlphaMissense	0.8851	likely pathogenic ✓ concordant with ClinVar
REVEL	0.391	indeterminate
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 8,082 bp · p 0.66 · regional, not allelic
Overall
CADD	26.9	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 0.000254% European (non-Finnish) · 3/1,179,998 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000682% 11/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)grpmax	0.000254%	393,332

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg392Thr
Coding: c.1175G>C
MANE Select: NM_001761
dbSNP: rs954539468
Type: single nucleotide variant
Location: chr16:2448935 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 1 PDB
Residue 392: a UniProt-annotated variant site (in ftdals5; uncertain significance; impaired degradation by the ubiquitin proteasome system (ups)); the cyclin n-terminal domain; an α-helix

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

Disease context

frontotemporal dementia and/or amyotrophic lateral sclerosis 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CCNF p.Ser621Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
CCNF p.Arg572Gln Uncertain significance ★★ ⚠ same condition
CCNF p.Ala146Thr Uncertain significance ★ ⚠ same condition
CCNF p.Arg21Gln Uncertain significance ★ ⚠ same condition
CCNF p.Arg572Leu Uncertain significance ★ ⚠ same condition
CCNF p.Gln302Pro Uncertain significance ★ same condition
CCNF p.Gly161Arg Uncertain significance ★ ⚠ same condition
CCNF p.His69Tyr Uncertain significance ★ ⚠ same condition

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-arg392thr (accessed [today's date]).

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