Is DENND4B p.Pro1148Arg (c.3443C>G) pathogenic?

DENND4B p.Pro1148Arg (c.3443C>G) is classified Uncertain significance in DENND4B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely benign (0.1246); Absent from gnomAD v4.1.

How common is DENND4B p.Pro1148Arg (c.3443C>G) in the general population?

DENND4B p.Pro1148Arg (c.3443C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND4B p.Pro1148Arg (c.3443C>G)?

AlphaMissense predicts likely benign (score 0.1246) — an in-silico prediction, not a clinical call.

DENND4B p.Pro1148Arg

c.3443C>G · rs2525651187 · VCV2276423

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1246 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1246	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -9.55	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 12	phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 3,204 bp · p 8.9e-14 · regional, not allelic
Overall
CADD	26.1	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: DENND4B
Protein: p.Pro1148Arg
Coding: c.3443C>G
MANE Select: NM_014856
dbSNP: rs2525651187
Type: single nucleotide variant
Location: chr1:153933207 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32

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-pro1148arg (accessed [today's date]).

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