Is DENND2B p.Leu725Val (c.2173C>G) pathogenic?

DENND2B p.Leu725Val (c.2173C>G) is classified Uncertain significance in DENND2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely benign (0.2981); Absent from gnomAD v4.1.

How common is DENND2B p.Leu725Val (c.2173C>G) in the general population?

DENND2B p.Leu725Val (c.2173C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND2B p.Leu725Val (c.2173C>G)?

AlphaMissense predicts likely benign (score 0.2981) — an in-silico prediction, not a clinical call.

DENND2B p.Leu725Val

c.2173C>G · rs1250776997 · VCV2619065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2981	likely benign
REVEL	0.188	benign-leaning
SaProt	LLR -4.84	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 5.9	GERP 0.88, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 21 kb · p 4.3e-17 · regional, not allelic
Overall
CADD	23.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DENND2B
Protein: p.Leu725Val
Coding: c.2173C>G
MANE Select: NM_213618
dbSNP: rs1250776997
Type: single nucleotide variant
Location: chr11:8711231 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 725: the udenn domain

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

Similar variants

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
DENND2B p.Ala113Gly 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/dennd2b-p-leu725val (accessed [today's date]).

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