Is DENND4B p.Ala281= (c.843G>A) pathogenic?

DENND4B p.Ala281= (c.843G>A) is classified Benign in DENND4B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-28). Low-frequency (popmax 2.6%, afr); Associated with DENND4B-related disorder.

What condition is associated with DENND4B p.Ala281= (c.843G>A)?

DENND4B p.Ala281= (c.843G>A) is associated with DENND4B-related disorder (ClinVar).

How common is DENND4B p.Ala281= (c.843G>A) in the general population?

DENND4B p.Ala281= (c.843G>A) is low-frequency (popmax 2.6%, afr) (gnomAD).

DENND4B p.Ala281=

c.843G>A · rs76818957 · VCV3045601

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 2.6%, afr)

Conditions

DENND4B-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.021	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12
Overall
CADD	2.553	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.6% African / African-American · 1,953/75,008 alleles

Filtering AF 2.51% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.47%

Overall 0.175% 2,828/1,612,892 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.6%	38
Remaining individualsnot grpmax-eligible	0.176%	568
Admixed American	0.134%	748
Middle Eastern	0.066%	1,515
European (non-Finnish)	0.0549%	1,820
East Asian	0.0312%	3,203
Finnishnot grpmax-eligible	0.0204%	4,905
South Asian	0.0066%	15,155

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.Ala281=
Coding: c.843G>A
MANE Select: NM_014856
dbSNP: rs76818957
Type: single nucleotide variant
Location: chr1:153942081 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32
Residue 281: the udenn domain

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

Disease context

DENND4B-related disorder

Similar variants

DENND4B p.Val103Ile Uncertain significance ★★ ⚠ same condition
DENND4B p.Ala16Thr Uncertain significance ★ ⚠ same condition
DENND4B p.Leu440Val Uncertain significance ★ ⚠ same condition
DENND4B p.Val121Met Uncertain significance ⚠ same condition
DENND4B c.1819+4T>C Likely benign same condition
DENND4B c.2439+10C>T Likely benign same condition
DENND4B c.3624-6C>T Likely benign same condition
DENND4B c.4115-3C>T Likely benign same condition

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-ala281 (accessed [today's date]).

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