Is CDCA4 p.Met40Leu (c.118A>T) pathogenic?

CDCA4 p.Met40Leu (c.118A>T) is classified Uncertain significance in CDCA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.7402); Ultra-rare (popmax 0.015%, amr).

How common is CDCA4 p.Met40Leu (c.118A>T) in the general population?

CDCA4 p.Met40Leu (c.118A>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about CDCA4 p.Met40Leu (c.118A>T)?

AlphaMissense predicts likely pathogenic (score 0.7402) — an in-silico prediction, not a clinical call.

CDCA4 p.Met40Leu

c.118A>T · rs200800804 · VCV3141013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7402 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7402	likely pathogenic
REVEL	0.265	benign-leaning
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 722 bp · p 0.12 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/60,020 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000868% 14/1,613,818 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,669
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.000169%	590,019

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: CDCA4
Protein: p.Met40Leu
Coding: c.118A>T
MANE Select: NM_017955
dbSNP: rs200800804
Type: single nucleotide variant
Location: chr14:105011812 (GRCh38)
Gene constraint: LOEUF 1.807 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 64.15
Residue 40: the serta domain

Full CDCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDCA4 p.Met40Ile Uncertain significance ★ ⚠ same residue
CDCA4 p.Ala135Val Uncertain significance ★ ⚠ same type
CDCA4 p.Ala145Pro Uncertain significance ★ ⚠ same type
CDCA4 p.Arg103His Uncertain significance ★ ⚠ same type
CDCA4 p.Arg152Gly Uncertain significance ★ ⚠ same type
CDCA4 p.Arg34Gln Uncertain significance ★ ⚠ same type
CDCA4 p.Arg80Cys Uncertain significance ★ ⚠ same type
CDCA4 p.Arg80Leu 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/cdca4-p-met40leu (accessed [today's date]).

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