Is DENND4A p.Leu1306Phe (c.3916C>T) pathogenic?

DENND4A p.Leu1306Phe (c.3916C>T) is classified Uncertain significance in DENND4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely benign (0.1128); Absent from gnomAD v4.1.

How common is DENND4A p.Leu1306Phe (c.3916C>T) in the general population?

DENND4A p.Leu1306Phe (c.3916C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND4A p.Leu1306Phe (c.3916C>T)?

AlphaMissense predicts likely benign (score 0.1128) — an in-silico prediction, not a clinical call.

DENND4A p.Leu1306Phe

c.3916C>T · VCV4010855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1128 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1128	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -7.87	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 9.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 31 kb · p 0.0012 · regional, not allelic
Overall
CADD	25.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L1262F vs ClinVar L1306F) — verify the residue.

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.Leu1306Phe
Coding: c.3916C>T
MANE Select: NM_001320835
Type: single nucleotide variant
Location: chr15:65690678 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.22
Residue 1306: the 'disordered' region

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-leu1306phe (accessed [today's date]).

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