Is DENND4A p.Pro729Arg (c.2186C>G) pathogenic?

DENND4A p.Pro729Arg (c.2186C>G) is classified Uncertain significance in DENND4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.1331); Absent from gnomAD v4.1.

How common is DENND4A p.Pro729Arg (c.2186C>G) in the general population?

DENND4A p.Pro729Arg (c.2186C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND4A p.Pro729Arg (c.2186C>G)?

AlphaMissense predicts likely benign (score 0.1331) — an in-silico prediction, not a clinical call.

DENND4A p.Pro729Arg

c.2186C>G · VCV4659519

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1331 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1331	likely benign
REVEL	0.257	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 10	GERP 2.8, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 54 kb · p 1.6e-13 · regional, not allelic
Overall
CADD	26.0	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: DENND4A
Protein: p.Pro729Arg
Coding: c.2186C>G
MANE Select: NM_001320835
Type: single nucleotide variant
Location: chr15:65702910 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.22

Full DENND4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DENND4A p.Ser696Arg Likely pathogenic ★ ⚠ same type
DENND4A p.Ala1108Glu Uncertain significance ★ ⚠ same type
DENND4A p.Ala1244Gly Uncertain significance ★ ⚠ same type
DENND4A p.Ala1476Gly Uncertain significance ★ ⚠ same type
DENND4A p.Ala1585Ser Uncertain significance ★ ⚠ same type
DENND4A p.Ala1619Pro Uncertain significance ★ ⚠ same type
DENND4A p.Ala324Gly Uncertain significance ★ ⚠ same type
DENND4A p.Ala596Pro 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/dennd4a-p-pro729arg (accessed [today's date]).

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