Is DENND4B p.Leu609Phe (c.1825C>T) pathogenic?

DENND4B p.Leu609Phe (c.1825C>T) is classified Likely pathogenic in DENND4B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2001-11-18). AlphaMissense: ambiguous (0.4821); Absent from gnomAD v4.1; Associated with Short stature.

What condition is associated with DENND4B p.Leu609Phe (c.1825C>T)?

DENND4B p.Leu609Phe (c.1825C>T) is associated with Short stature (ClinVar).

How common is DENND4B p.Leu609Phe (c.1825C>T) in the general population?

DENND4B p.Leu609Phe (c.1825C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND4B p.Leu609Phe (c.1825C>T)?

AlphaMissense predicts ambiguous (score 0.4821) — an in-silico prediction, not a clinical call.

DENND4B p.Leu609Phe

c.1825C>T · rs1557853919 · VCV599505

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4821 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Short stature

Computational evidence

Protein change
AlphaMissense	0.4821	ambiguous
REVEL	0.39	indeterminate
SaProt	LLR -13.30	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 9,410 bp · p 1.8e-22 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

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.Leu609Phe
Coding: c.1825C>T
MANE Select: NM_014856
dbSNP: rs1557853919
Type: single nucleotide variant
Location: chr1:153939040 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32
Residue 609: the ddenn domain

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

Disease context

Short stature — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DENND4B p.Trp943Ser Conflicting classifications of pathogenicity ⚠ same condition
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

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-leu609phe (accessed [today's date]).

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