Is CDC5L p.Glu213Asp (c.639A>C) pathogenic?

CDC5L p.Glu213Asp (c.639A>C) is classified Uncertain significance in CDC5L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-11). AlphaMissense: likely pathogenic (0.863); Very rare (popmax 0.00305%, nfe).

How common is CDC5L p.Glu213Asp (c.639A>C) in the general population?

CDC5L p.Glu213Asp (c.639A>C) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about CDC5L p.Glu213Asp (c.639A>C)?

AlphaMissense predicts likely pathogenic (score 0.863) — an in-silico prediction, not a clinical call.

CDC5L p.Glu213Asp

c.639A>C · VCV3998630

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.863	likely pathogenic
REVEL	0.165	moderately benign-leaning
SaProt	LLR -10.11	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.25, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 43 kb · p 4.7e-09 · regional, not allelic
Overall
CADD	23.6	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 0.00305% European (non-Finnish) · 36/1,179,712 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00267% 39/1,461,374 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,832
European (non-Finnish)grpmax	0.00305%	32,770

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: CDC5L
Protein: p.Glu213Asp
Coding: c.639A>C
MANE Select: NM_001253
Type: single nucleotide variant
Location: chr6:44403908 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 41 PDB

Full CDC5L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC5L p.Ala93= Benign ★★ same type
CDC5L p.Asp236= Benign ★★ same type
CDC5L p.Leu721= Benign ★★ same type
CDC5L p.Ala234Val Uncertain significance ★ ⚠ same type
CDC5L p.Ala457Thr Uncertain significance ★ ⚠ same type
CDC5L p.Ala485Thr Uncertain significance ★ ⚠ same type
CDC5L p.Arg202Lys Uncertain significance ★ ⚠ same type
CDC5L p.Arg202Thr 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/cdc5l-p-glu213asp (accessed [today's date]).

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