Is CCNF p.Ala146Thr (c.436G>A) pathogenic?

CCNF p.Ala146Thr (c.436G>A) is classified Uncertain significance in CCNF (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.0665); Very rare (popmax 0.00167%, amr); Associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 5.

What condition is associated with CCNF p.Ala146Thr (c.436G>A)?

CCNF p.Ala146Thr (c.436G>A) is associated with frontotemporal dementia and/or amyotrophic lateral sclerosis 5 (ClinVar).

How common is CCNF p.Ala146Thr (c.436G>A) in the general population?

CCNF p.Ala146Thr (c.436G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CCNF p.Ala146Thr (c.436G>A)?

AlphaMissense predicts likely benign (score 0.0665) — an in-silico prediction, not a clinical call.

CCNF p.Ala146Thr

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.436G>A · rs749253539 · VCV2627498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontotemporal dementia and/or amyotrophic lateral sclerosis 5

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -5.24	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 0.68	GERP -3.7
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0017 · regional, not allelic
Overall
CADD	0.966	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 0.00167% Admixed American · 1/59,994 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000548% 8/1,460,440 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,994
Finnishnot grpmax-eligible	0.00158%	63,370
European (non-Finnish)	0.000509%	196,581

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.Ala146Thr
Coding: c.436G>A
MANE Select: NM_001761
dbSNP: rs749253539
Type: single nucleotide variant
Location: chr16:2437218 (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

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.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
CCNF p.Arg392Thr Pathogenic ⚠ 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-ala146thr (accessed [today's date]).

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