Is DENND4B p.Arg8Trp (c.22C>T) pathogenic?

DENND4B p.Arg8Trp (c.22C>T) is classified Uncertain significance in DENND4B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: ambiguous (0.3497); Very rare (popmax 0.00227%, eas).

How common is DENND4B p.Arg8Trp (c.22C>T) in the general population?

DENND4B p.Arg8Trp (c.22C>T) is very rare (popmax 0.00227%, eas) (gnomAD).

What do computational predictors say about DENND4B p.Arg8Trp (c.22C>T)?

AlphaMissense predicts ambiguous (score 0.3497) — an in-silico prediction, not a clinical call.

DENND4B p.Arg8Trp

c.22C>T · VCV3501025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00227%, eas)

Computational evidence

Protein change
AlphaMissense	0.3497	ambiguous
REVEL	0.335	indeterminate
SaProt	LLR -13.69	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 9,410 bp · p 1.8e-22 · regional, not allelic
Overall
CADD	31.0	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 0.00227% East Asian · 1/43,992 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000276% 4/1,446,966 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00227%	43,992
Admixed American	0.00172%	58,196
European (non-Finnish)	0.00017%	586,548

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.Arg8Trp
Coding: c.22C>T
MANE Select: NM_014856
Type: single nucleotide variant
Location: chr1:153944353 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32

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

Similar variants

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
DENND4B p.Ala275Thr 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-arg8trp (accessed [today's date]).

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