Is DENND5B p.Pro384Ala (c.1150C>G) pathogenic?

DENND5B p.Pro384Ala (c.1150C>G) is classified Uncertain significance in DENND5B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.6924); Very rare (popmax 0.000254%, nfe).

How common is DENND5B p.Pro384Ala (c.1150C>G) in the general population?

DENND5B p.Pro384Ala (c.1150C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DENND5B p.Pro384Ala (c.1150C>G)?

AlphaMissense predicts likely pathogenic (score 0.6924) — an in-silico prediction, not a clinical call.

DENND5B p.Pro384Ala

c.1150C>G · VCV4077334

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6924 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6924	likely pathogenic
REVEL	0.349	indeterminate
SaProt	LLR -8.26	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 164 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	25.8	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 0.000254% European (non-Finnish) · 3/1,179,438 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,460,202 alleles · very rare

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: DENND5B
Protein: p.Pro384Ala
Coding: c.1150C>G
MANE Select: NM_144973
Type: single nucleotide variant
Location: chr12:31452419 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.12
Residue 384: the cdenn domain

Full DENND5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DENND5B p.His852Tyr Pathogenic/Likely pathogenic ★★ ⚠ same type
DENND5B p.Glu381Lys Uncertain significance ★★ ⚠ same type
DENND5B p.Ile372Thr Uncertain significance ★★ ⚠ same type
DENND5B p.Pro237Ser Uncertain significance ★★ ⚠ same type
DENND5B p.Val26Met Uncertain significance ★★ ⚠ same type
DENND5B p.Glu774Gly Pathogenic ★ ⚠ same type
DENND5B c.128-3722A>C Uncertain significance ★ same type
DENND5B c.1861+2T>A 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/dennd5b-p-pro384ala (accessed [today's date]).

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