Is CCNF p.Arg140Gln (c.419G>A) pathogenic?

CCNF p.Arg140Gln (c.419G>A) is classified Uncertain significance in CCNF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-01). AlphaMissense: likely benign (0.0728); Ultra-rare (popmax 0.048%, afr); Associated with amyotrophic lateral sclerosis.

What condition is associated with CCNF p.Arg140Gln (c.419G>A)?

CCNF p.Arg140Gln (c.419G>A) is associated with amyotrophic lateral sclerosis (ClinVar).

How common is CCNF p.Arg140Gln (c.419G>A) in the general population?

CCNF p.Arg140Gln (c.419G>A) is ultra-rare (popmax 0.048%, afr) (gnomAD).

How is Amyotrophic lateral sclerosis inherited?

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

What do computational predictors say about CCNF p.Arg140Gln (c.419G>A)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

CCNF p.Arg140Gln

c.419G>A · rs371783851 · VCV1343313

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.048%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis

Computational evidence

Protein change
AlphaMissense	0.0728	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -6.79	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 5.1	GERP -1.6, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0017 · regional, not allelic
Overall
CADD	17.68	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 0.048% African / African-American · 36/74,936 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.0026% 42/1,612,664 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.048%	2,082
Middle Eastern	0.0164%	6,084
Admixed American	0.00334%	29,984
East Asian	0.00223%	44,846
European (non-Finnish)	0.00017%	589,623

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.Arg140Gln
Coding: c.419G>A
MANE Select: NM_001761
dbSNP: rs371783851
Type: single nucleotide variant
Location: chr16:2437201 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 1 PDB
Residue 140: an α-helix

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

Disease context

amyotrophic lateral sclerosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amyotrophic lateral sclerosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CCNF p.Arg140Trp Uncertain significance ★ ⚠ same residue
CCNF p.Val640Met Uncertain significance ★ ⚠ same condition
CCNF p.Glu575Asp Likely benign ★ ⚠ same condition
CCNF p.Leu209Val Likely benign ★ ⚠ same condition
CCNF p.Ser621Gly Pathogenic/Likely pathogenic ★★ ⚠ same type
CCNF p.Arg24Lys Uncertain significance ★★ ⚠ same type
CCNF p.Arg572Gln Uncertain significance ★★ ⚠ same type
CCNF p.Gly254Ala Uncertain significance ★★ ⚠ 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-arg140gln (accessed [today's date]).

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