Is DENND4B p.Gln63Pro (c.188A>C) pathogenic?

DENND4B p.Gln63Pro (c.188A>C) is classified Uncertain significance in DENND4B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-06). AlphaMissense: likely benign (0.079); Very rare (popmax 0.00127%, nfe).

How common is DENND4B p.Gln63Pro (c.188A>C) in the general population?

DENND4B p.Gln63Pro (c.188A>C) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about DENND4B p.Gln63Pro (c.188A>C)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

DENND4B p.Gln63Pro

c.188A>C · rs2525836020 · VCV2333509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -4.02	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 7.9	phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 9,410 bp · p 1.8e-22 · regional, not allelic
Overall
CADD	24.7	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

Grpmax group 0.00127% European (non-Finnish) · 15/1,179,256 alleles

Filtering AF 0.000764% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.00103% 15/1,460,154 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: DENND4B
Protein: p.Gln63Pro
Coding: c.188A>C
MANE Select: NM_014856
dbSNP: rs2525836020
Type: single nucleotide variant
Location: chr1:153944187 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32
Residue 63: the mabp domain

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

Similar variants

DENND4B p.Arg561Trp Uncertain significance ★★ ⚠ same type
DENND4B p.Val103Ile Uncertain significance ★★ ⚠ same type
DENND4B p.Ala1089Val Uncertain significance ★ ⚠ same type
DENND4B p.Ala1113Val Uncertain significance ★ ⚠ same type
DENND4B p.Ala1408Val Uncertain significance ★ ⚠ same type
DENND4B p.Ala150Thr Uncertain significance ★ ⚠ same type
DENND4B p.Ala16Thr Uncertain significance ★ ⚠ same type
DENND4B p.Ala275Thr 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/dennd4b-p-gln63pro (accessed [today's date]).

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