Is CDC7 p.Met333Val (c.997A>G) pathogenic?

CDC7 p.Met333Val (c.997A>G) is classified Uncertain significance in CDC7 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely benign (0.0579); Very rare (popmax 0.00966%, nfe).

How common is CDC7 p.Met333Val (c.997A>G) in the general population?

CDC7 p.Met333Val (c.997A>G) is very rare (popmax 0.00966%, nfe) (gnomAD).

What do computational predictors say about CDC7 p.Met333Val (c.997A>G)?

AlphaMissense predicts likely benign (score 0.0579) — an in-silico prediction, not a clinical call.

CDC7 p.Met333Val

c.997A>G · rs778964691 · VCV2208716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0579 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00966%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0579	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -5.19	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 -0.97	GERP -0.89
Regional constraint	o/e 0.87	unconstrained · MANE · 23 kb · p 0.001 · regional, not allelic
Overall
CADD	0.054	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 0.00966% European (non-Finnish) · 114/1,179,666 alleles

Filtering AF 0.00818% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00761%

Overall 0.00744% 120/1,613,574 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00966%	10,348
Remaining individualsnot grpmax-eligible	0.0096%	10,412

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: CDC7
Protein: p.Met333Val
Coding: c.997A>G
MANE Select: NM_003503
dbSNP: rs778964691
Type: single nucleotide variant
Location: chr1:91514897 (GRCh38)
Gene constraint: LOEUF 0.889 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.49 · 9 PDB
Residue 333: the protein kinase domain

Full CDC7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC7 p.Met333Thr Uncertain significance ★ ⚠ same residue
CDC7 c.-124A>G Benign ★★ same type
CDC7 p.Ala254Gly Uncertain significance ★ ⚠ same type
CDC7 p.Ala254Ser Uncertain significance ★ ⚠ same type
CDC7 p.Ala355Val Uncertain significance ★ ⚠ same type
CDC7 p.Ala38Glu Uncertain significance ★ ⚠ same type
CDC7 p.Ala38Thr Uncertain significance ★ ⚠ same type
CDC7 p.Ala50Val 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/cdc7-p-met333val (accessed [today's date]).

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