Is DENND2B p.Pro73Ala (c.217C>G) pathogenic?

DENND2B p.Pro73Ala (c.217C>G) is classified Uncertain significance in DENND2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.0513); Absent from gnomAD v4.1.

How common is DENND2B p.Pro73Ala (c.217C>G) in the general population?

DENND2B p.Pro73Ala (c.217C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND2B p.Pro73Ala (c.217C>G)?

AlphaMissense predicts likely benign (score 0.0513) — an in-silico prediction, not a clinical call.

DENND2B p.Pro73Ala

c.217C>G · VCV4010781

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0513 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0513	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.49	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 0.25	GERP -3.5, phastCons 0.001
Regional constraint	o/e 1.01	unconstrained · MANE · 36 kb · p 0.75 · regional, not allelic
Overall
CADD	0.152	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.Pro73Ala
Coding: c.217C>G
MANE Select: NM_213618
Type: single nucleotide variant
Location: chr11:8731073 (GRCh38)
Gene constraint: LOEUF 0.373 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 58.86
Residue 73: the 'disordered' region

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-pro73ala (accessed [today's date]).

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