Is CDC5L p.Arg727His (c.2180G>A) pathogenic?

CDC5L p.Arg727His (c.2180G>A) is classified Uncertain significance in CDC5L (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-06). AlphaMissense: likely pathogenic (0.8313); Very rare (popmax 0.004%, afr).

How common is CDC5L p.Arg727His (c.2180G>A) in the general population?

CDC5L p.Arg727His (c.2180G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CDC5L p.Arg727His (c.2180G>A)?

AlphaMissense predicts likely pathogenic (score 0.8313) — an in-silico prediction, not a clinical call.

CDC5L p.Arg727His

c.2180G>A · rs1296778518 · VCV2317382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8313 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8313	likely pathogenic
REVEL	0.439	indeterminate
SaProt	LLR -13.25	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.53, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 43 kb · p 4.7e-09 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.004% African / African-American · 3/74,922 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000496% 8/1,613,972 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,974
Admixed American	0.00333%	29,997
Finnishnot grpmax-eligible	0.00156%	64,020
South Asian	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,179,976

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.Arg727His
Coding: c.2180G>A
MANE Select: NM_001253
dbSNP: rs1296778518
Type: single nucleotide variant
Location: chr6:44445743 (GRCh38)
Gene constraint: LOEUF 0.26 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.94 · 41 PDB
Residue 727: the 'interaction with plrg1' region; an α-helix

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-arg727his (accessed [today's date]).

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