Is DENND2B p.Val883Ala (c.2648T>C) pathogenic?

DENND2B p.Val883Ala (c.2648T>C) is classified Likely benign in DENND2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: ambiguous (0.3452); Rare (popmax 0.652%, nfe).

How common is DENND2B p.Val883Ala (c.2648T>C) in the general population?

DENND2B p.Val883Ala (c.2648T>C) is rare (popmax 0.652%, nfe) (gnomAD).

What do computational predictors say about DENND2B p.Val883Ala (c.2648T>C)?

AlphaMissense predicts ambiguous (score 0.3452) — an in-silico prediction, not a clinical call.

DENND2B p.Val883Ala

c.2648T>C · rs113126215 · VCV2641582

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3452 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.652%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3452	ambiguous
REVEL	0.38	indeterminate
SaProt	LLR -8.94	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 21 kb · p 4.3e-17 · regional, not allelic
Overall
CADD	24.8	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 0.652% European (non-Finnish) · 7,699/1,180,018 alleles

Filtering AF 0.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.635%

Overall 0.597% 9,639/1,613,966 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.29%	44
European (non-Finnish)grpmax	0.652%	153
Remaining individualsnot grpmax-eligible	0.408%	245
African / African-American	0.117%	853
Admixed American	0.11%	909
South Asian	0.0725%	1,380
Middle Eastern	0.033%	3,031
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DENND2B
Protein: p.Val883Ala
Coding: c.2648T>C
MANE Select: NM_213618
dbSNP: rs113126215
Type: single nucleotide variant
Location: chr11:8702644 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 883: the cdenn domain

Full DENND2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DENND2B p.Val883Met Uncertain significance ★ ⚠ same residue
DENND2B p.Arg312Gln Uncertain significance ★★ ⚠ same type
DENND2B c.3379+7G>A Benign ★★ same type
DENND2B c.81-4C>A Benign/Likely benign ★★ same type
DENND2B p.Ala823Thr Benign ★★ same type
DENND2B p.Arg250Gln Benign ★★ same type
DENND2B p.His670= Benign ★★ same type
DENND2B p.Pro420= Benign ★★ 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/dennd2b-p-val883ala (accessed [today's date]).

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