Is DDN p.Arg583Gly (c.1747A>G) pathogenic?

DDN p.Arg583Gly (c.1747A>G) is classified Uncertain significance in DDN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely benign (0.0648); Ultra-rare (popmax 0.0243%, amr).

How common is DDN p.Arg583Gly (c.1747A>G) in the general population?

DDN p.Arg583Gly (c.1747A>G) is ultra-rare (popmax 0.0243%, amr) (gnomAD).

What do computational predictors say about DDN p.Arg583Gly (c.1747A>G)?

AlphaMissense predicts likely benign (score 0.0648) — an in-silico prediction, not a clinical call.

DDN p.Arg583Gly

c.1747A>G · rs139973689 · VCV2364904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0243%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0648	likely benign
REVEL	0.004	strongly benign-leaning
SaProt	LLR -5.81	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 -6.1	GERP -3.8
Regional constraint	o/e 0.96	unconstrained · MANE · 2,544 bp · p 0.18 · regional, not allelic
Overall
CADD	0.092	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 0.0243% Admixed American · 11/45,340 alleles

Filtering AF 0.0217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.0194% 296/1,527,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0243%	4,122
European (non-Finnish)	0.0241%	4,156
Remaining individualsnot grpmax-eligible	0.0171%	5,862

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: DDN
Protein: p.Arg583Gly
Coding: c.1747A>G
MANE Select: NM_015086
dbSNP: rs139973689
Type: single nucleotide variant
Location: chr12:48997129 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 46.28
Residue 583: the 'interaction with cd2ap and nphs1' region; the 'disordered' region

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

Similar variants

DDN p.Glu661Gly Benign ★★ same type
DDN p.Pro358Arg Benign ★★ same type
DDN p.Ala154Thr Uncertain significance ★ ⚠ same type
DDN p.Ala169Val Uncertain significance ★ ⚠ same type
DDN p.Ala174Glu Uncertain significance ★ ⚠ same type
DDN p.Ala179Thr Uncertain significance ★ ⚠ same type
DDN p.Ala305Thr Uncertain significance ★ ⚠ same type
DDN p.Ala341Thr 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/ddn-p-arg583gly (accessed [today's date]).

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