Is CDC5L p.Pro462Thr (c.1384C>A) pathogenic?

CDC5L p.Pro462Thr (c.1384C>A) is classified Uncertain significance in CDC5L (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.0999); Very rare (popmax 0.00645%, nfe).

How common is CDC5L p.Pro462Thr (c.1384C>A) in the general population?

CDC5L p.Pro462Thr (c.1384C>A) is very rare (popmax 0.00645%, nfe) (gnomAD).

What do computational predictors say about CDC5L p.Pro462Thr (c.1384C>A)?

AlphaMissense predicts likely benign (score 0.0999) — an in-silico prediction, not a clinical call.

CDC5L p.Pro462Thr

c.1384C>A · VCV4650904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00645%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0999	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -6.77	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 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 43 kb · p 4.7e-09 · regional, not allelic
Overall
CADD	22.4	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 0.00645% European (non-Finnish) · 76/1,178,362 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00497% 80/1,610,500 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00645%	15,505
Remaining individualsnot grpmax-eligible	0.00481%	20,776
African / African-American	0.00134%	74,718

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.Pro462Thr
Coding: c.1384C>A
MANE Select: NM_001253
Type: single nucleotide variant
Location: chr6:44422789 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 41 PDB
Residue 462: the 'interaction with ppp1r8' region

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-pro462thr (accessed [today's date]).

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