Is CDC40 p.Met246Ile (c.738G>A) pathogenic?

CDC40 p.Met246Ile (c.738G>A) is classified Uncertain significance in CDC40 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.258); Ultra-rare (popmax 0.0573%, afr).

How common is CDC40 p.Met246Ile (c.738G>A) in the general population?

CDC40 p.Met246Ile (c.738G>A) is ultra-rare (popmax 0.0573%, afr) (gnomAD).

What do computational predictors say about CDC40 p.Met246Ile (c.738G>A)?

AlphaMissense predicts likely benign (score 0.258) — an in-silico prediction, not a clinical call.

CDC40 p.Met246Ile

c.738G>A · VCV4223263

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.258 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0573%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.258	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.34	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 39 kb · p 5.5e-07 · regional, not allelic
Overall
CADD	23.4	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 0.0573% African / African-American · 43/75,004 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.039%

Overall 0.00335% 54/1,612,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0573%	1,744
Remaining individualsnot grpmax-eligible	0.0096%	10,412
Admixed American	0.005%	19,984
East Asian	0.00446%	22,423

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: CDC40
Protein: p.Met246Ile
Coding: c.738G>A
MANE Select: NM_015891
Type: single nucleotide variant
Location: chr6:110212143 (GRCh38)
Gene constraint: LOEUF 0.491 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 86.76 · 30 PDB
Residue 246: a β-strand

Full CDC40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC40 p.Ala33Gly Uncertain significance ★ ⚠ same type
CDC40 p.Ala466Thr Uncertain significance ★ ⚠ same type
CDC40 p.Arg129Lys Uncertain significance ★ ⚠ same type
CDC40 p.Arg322Trp Uncertain significance ★ ⚠ same type
CDC40 p.Arg323Cys Uncertain significance ★ ⚠ same type
CDC40 p.Asn382His Uncertain significance ★ ⚠ same type
CDC40 p.Asn430Lys Uncertain significance ★ ⚠ same type
CDC40 p.Asn497Thr 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/cdc40-p-met246ile (accessed [today's date]).

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