Is DEDD2 p.Arg321Cys (c.961C>T) pathogenic?

DEDD2 p.Arg321Cys (c.961C>T) is classified Uncertain significance in DEDD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-27). AlphaMissense: likely benign (0.1247); Ultra-rare (popmax 0.0556%, amr).

How common is DEDD2 p.Arg321Cys (c.961C>T) in the general population?

DEDD2 p.Arg321Cys (c.961C>T) is ultra-rare (popmax 0.0556%, amr) (gnomAD).

What do computational predictors say about DEDD2 p.Arg321Cys (c.961C>T)?

AlphaMissense predicts likely benign (score 0.1247) — an in-silico prediction, not a clinical call.

DEDD2 p.Arg321Cys

c.961C>T · rs1191081808 · VCV2291872

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1247 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0556%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1247	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -7.50	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 4.6	GERP 1.1, phastCons 0.99
Regional constraint	o/e 0.68	unconstrained · MANE · 10 kb · p 9.8e-06 · regional, not allelic
Overall
CADD	19.65	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 0.0556% Admixed American · 33/59,314 alleles

Filtering AF 0.0407% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0355%

Overall 0.00473% 76/1,605,956 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0556%	1,797
Remaining individualsnot grpmax-eligible	0.00483%	20,713
European (non-Finnish)	0.00323%	30,976
African / African-American	0.00134%	74,776
South Asian	0.0011%	90,628

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: DEDD2
Protein: p.Arg321Cys
Coding: c.961C>T
MANE Select: NM_133328
dbSNP: rs1191081808
Type: single nucleotide variant
Location: chr19:42199458 (GRCh38)
Gene constraint: LOEUF 1.12 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.80

Full DEDD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEDD2 p.Arg321His Uncertain significance ★ ⚠ same residue
DEDD2 p.Ala103Glu Uncertain significance ★ ⚠ same type
DEDD2 p.Ala177Val Uncertain significance ★ ⚠ same type
DEDD2 p.Ala52Val Uncertain significance ★ ⚠ same type
DEDD2 p.Arg114Cys Uncertain significance ★ ⚠ same type
DEDD2 p.Arg131Cys Uncertain significance ★ ⚠ same type
DEDD2 p.Arg132Cys Uncertain significance ★ ⚠ same type
DEDD2 p.Arg132His 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/dedd2-p-arg321cys (accessed [today's date]).

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