Is DBNDD2 p.Leu16Phe (c.46C>T) pathogenic?

DBNDD2 p.Leu16Phe (c.46C>T) is classified Uncertain significance in DBNDD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-01). AlphaMissense: ambiguous (0.5437); Ultra-rare (popmax 0.0546%, afr).

How common is DBNDD2 p.Leu16Phe (c.46C>T) in the general population?

DBNDD2 p.Leu16Phe (c.46C>T) is ultra-rare (popmax 0.0546%, afr) (gnomAD).

What do computational predictors say about DBNDD2 p.Leu16Phe (c.46C>T)?

AlphaMissense predicts ambiguous (score 0.5437) — an in-silico prediction, not a clinical call.

DBNDD2 p.Leu16Phe

c.46C>T · VCV4237732

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5437 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0546%, afr)

Computational evidence

Protein change
AlphaMissense	0.5437	ambiguous
REVEL	0.299	indeterminate
SaProt	LLR -7.60	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.5, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,669 bp · p 0.4 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L114F vs ClinVar L16F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0546% African / African-American · 41/75,072 alleles

Filtering AF 0.0413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.00316% 51/1,614,276 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0546%	1,831
Admixed American	0.0117%	8,577
Remaining individualsnot grpmax-eligible	0.0048%	20,837

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: DBNDD2
Protein: p.Leu16Phe
Coding: c.46C>T
MANE Select: NM_001048225
Type: single nucleotide variant
Location: chr20:45408513 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 60.09

Full DBNDD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DBNDD2 c.78G>T Uncertain significance ★ same type
DBNDD2 c.95C>A Uncertain significance ★ same type
DBNDD2 c.-146C>T Uncertain significance ★ same type
DBNDD2 c.-15C>A Uncertain significance ★ ⚠ same type
DBNDD2 c.-29G>T Uncertain significance ★ ⚠ same type
DBNDD2 c.-32C>T Uncertain significance ★ ⚠ same type
DBNDD2 c.-5C>A Uncertain significance ★ ⚠ same type
DBNDD2 c.-5C>T 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/dbndd2-p-leu16phe (accessed [today's date]).

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