Is DENND4B p.Arg1069Cys (c.3205C>T) pathogenic?

DENND4B p.Arg1069Cys (c.3205C>T) is classified Uncertain significance in DENND4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely benign (0.1452); Very rare (popmax 0.00602%, amr).

How common is DENND4B p.Arg1069Cys (c.3205C>T) in the general population?

DENND4B p.Arg1069Cys (c.3205C>T) is very rare (popmax 0.00602%, amr) (gnomAD).

What do computational predictors say about DENND4B p.Arg1069Cys (c.3205C>T)?

AlphaMissense predicts likely benign (score 0.1452) — an in-silico prediction, not a clinical call.

DENND4B p.Arg1069Cys

c.3205C>T · VCV4010875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1452 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00602%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1452	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -10.73	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 1,458 bp · p 0.63 · regional, not allelic
Overall
CADD	32.0	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 0.00602% Admixed American · 3/49,858 alleles

Filtering AF 0.0016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000842%

Overall 0.000579% 9/1,554,200 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00602%	16,619
Ashkenazi Jewishnot grpmax-eligible	0.00391%	25,592
East Asian	0.00227%	44,148
Remaining individualsnot grpmax-eligible	0.00167%	59,936
Finnishnot grpmax-eligible	0.00165%	60,434
European (non-Finnish)	0.000173%	576,741

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: DENND4B
Protein: p.Arg1069Cys
Coding: c.3205C>T
MANE Select: NM_014856
Type: single nucleotide variant
Location: chr1:153933608 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32
Residue 1069: the 'disordered' region

Full DENND4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DENND4B p.Arg1069His Uncertain significance ★ ⚠ same residue
DENND4B p.Arg561Trp Uncertain significance ★★ ⚠ same type
DENND4B p.Val103Ile Uncertain significance ★★ ⚠ same type
DENND4B p.Ala1089Val Uncertain significance ★ ⚠ same type
DENND4B p.Ala1113Val Uncertain significance ★ ⚠ same type
DENND4B p.Ala1408Val Uncertain significance ★ ⚠ same type
DENND4B p.Ala150Thr Uncertain significance ★ ⚠ same type
DENND4B p.Ala16Thr 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/dennd4b-p-arg1069cys (accessed [today's date]).

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