Is CCNF p.Val640Met (c.1918G>A) pathogenic?

CCNF p.Val640Met (c.1918G>A) is classified Uncertain significance in CCNF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-01). AlphaMissense: likely benign (0.0991); Very rare (popmax 0.00234%, nfe); Associated with amyotrophic lateral sclerosis.

What condition is associated with CCNF p.Val640Met (c.1918G>A)?

CCNF p.Val640Met (c.1918G>A) is associated with amyotrophic lateral sclerosis (ClinVar).

How common is CCNF p.Val640Met (c.1918G>A) in the general population?

CCNF p.Val640Met (c.1918G>A) is very rare (popmax 0.00234%, nfe) (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.Val640Met (c.1918G>A)?

AlphaMissense predicts likely benign (score 0.0991) — an in-silico prediction, not a clinical call.

CCNF p.Val640Met

c.1918G>A · rs373872375 · VCV1343314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00234%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis

Computational evidence

Protein change
AlphaMissense	0.0991	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -7.90	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 0.53, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 8,082 bp · p 0.66 · regional, not allelic
Overall
CADD	19.48	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 0.00234% European (non-Finnish) · 27/1,154,934 alleles

Filtering AF 0.0016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00218% 34/1,560,636 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00666%	15,022
Finnishnot grpmax-eligible	0.00489%	20,435
European (non-Finnish)grpmax	0.00234%	42,775

Remaining individuals 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.Val640Met
Coding: c.1918G>A
MANE Select: NM_001761
dbSNP: rs373872375
Type: single nucleotide variant
Location: chr16:2456577 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.70 (gnomAD)
Structure: AlphaFold pLDDT 72.34 · 1 PDB
Residue 640: the 'pest' region

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.Arg140Gln 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
CCNF p.Gly719Val 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-val640met (accessed [today's date]).

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