Is DENND6B p.Arg464Cys (c.1390C>T) pathogenic?

DENND6B p.Arg464Cys (c.1390C>T) is classified Uncertain significance in DENND6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.072); Ultra-rare (popmax 0.0166%, mid).

How common is DENND6B p.Arg464Cys (c.1390C>T) in the general population?

DENND6B p.Arg464Cys (c.1390C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about DENND6B p.Arg464Cys (c.1390C>T)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

DENND6B p.Arg464Cys

c.1390C>T · VCV4239617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -8.84	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 2.9	GERP 1.5, phastCons 0.18
Regional constraint	o/e 0.91	unconstrained · MANE · 15 kb · p 0.012 · regional, not allelic
Overall
CADD	23.5	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 0.0166% Middle Eastern · 1/6,012 alleles

Filtering AF 0.00831% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00645%

Overall 0.00551% 86/1,560,060 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,012
African / African-American	0.015%	6,676
European (non-Finnish)	0.00616%	16,237
Remaining individualsnot grpmax-eligible	0.0033%	30,263
South Asian	0.00118%	84,532

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: DENND6B
Protein: p.Arg464Cys
Coding: c.1390C>T
MANE Select: NM_001001794
Type: single nucleotide variant
Location: chr22:50313066 (GRCh38)
Gene constraint: LOEUF 1.212 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.35
Residue 464: the ddenn domain

Full DENND6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DENND6B p.Arg464His Uncertain significance ★ ⚠ same residue
DENND6B p.Ala181Glu Uncertain significance ★ ⚠ same type
DENND6B p.Ala196Val Uncertain significance ★ ⚠ same type
DENND6B p.Ala19Pro Uncertain significance ★ ⚠ same type
DENND6B p.Ala384Thr Uncertain significance ★ ⚠ same type
DENND6B p.Ala394Val Uncertain significance ★ ⚠ same type
DENND6B p.Ala3Pro Uncertain significance ★ ⚠ same type
DENND6B p.Ala506Thr 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/dennd6b-p-arg464cys (accessed [today's date]).

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