Is DENND5A p.Pro399Leu (c.1196C>T) pathogenic?

DENND5A p.Pro399Leu (c.1196C>T) is classified Uncertain significance in DENND5A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.8494); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with DENND5A p.Pro399Leu (c.1196C>T)?

DENND5A p.Pro399Leu (c.1196C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DENND5A p.Pro399Leu (c.1196C>T) in the general population?

DENND5A p.Pro399Leu (c.1196C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND5A p.Pro399Leu (c.1196C>T)?

AlphaMissense predicts likely pathogenic (score 0.8494) — an in-silico prediction, not a clinical call.

DENND5A p.Pro399Leu

c.1196C>T · VCV4239572

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8494 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8494	likely pathogenic
REVEL	0.478	indeterminate
SaProt	LLR -10.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 86 kb · p 0.00094 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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: DENND5A
Protein: p.Pro399Leu
Coding: c.1196C>T
MANE Select: NM_015213
Type: single nucleotide variant
Location: chr11:9181026 (GRCh38)
Gene constraint: LOEUF 0.574 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.74
Residue 399: the cdenn domain

Full DENND5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DENND5A p.Ala355Pro Uncertain significance ★★ ⚠ same condition
DENND5A p.Arg1159Trp Uncertain significance ★★ ⚠ same condition
DENND5A p.Arg1265His Uncertain significance ★★ ⚠ same condition
DENND5A p.Arg198Leu Uncertain significance ★★ same condition
DENND5A p.Arg198Trp Uncertain significance ★★ same condition
DENND5A p.Arg220Gln Uncertain significance ★★ ⚠ same condition
DENND5A p.Arg371Trp Uncertain significance ★★ ⚠ same condition
DENND5A p.Arg439Gln Uncertain significance ★★ ⚠ same condition

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/dennd5a-p-pro399leu (accessed [today's date]).

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