Is DENND4B p.Pro230= (c.690C>T) pathogenic?

DENND4B p.Pro230= (c.690C>T) is classified Likely benign in DENND4B (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-04-26). Ultra-rare (popmax 0.0147%, afr); Associated with DENND4B-related disorder.

What condition is associated with DENND4B p.Pro230= (c.690C>T)?

DENND4B p.Pro230= (c.690C>T) is associated with DENND4B-related disorder (ClinVar).

How common is DENND4B p.Pro230= (c.690C>T) in the general population?

DENND4B p.Pro230= (c.690C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

DENND4B p.Pro230=

c.690C>T · rs201629916 · VCV3057373

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Conditions

DENND4B-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP -9.3
Overall
CADD	4.417	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,904 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00285% 46/1,613,580 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,809
East Asian	0.00669%	14,957
Finnishnot grpmax-eligible	0.00469%	21,300
European (non-Finnish)	0.0022%	45,377
Admixed American	0.00167%	59,970
Remaining individualsnot grpmax-eligible	0.0016%	62,462
South Asian	0.0011%	91,080

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: DENND4B
Protein: p.Pro230=
Coding: c.690C>T
MANE Select: NM_014856
dbSNP: rs201629916
Type: single nucleotide variant
Location: chr1:153942307 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32
Residue 230: the udenn domain

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

Disease context

DENND4B-related disorder

Similar variants

DENND4B p.Val103Ile Uncertain significance ★★ ⚠ same condition
DENND4B p.Ala16Thr Uncertain significance ★ same condition
DENND4B p.Leu440Val Uncertain significance ★ ⚠ same condition
DENND4B p.Val121Met Uncertain significance ⚠ same condition
DENND4B c.1819+4T>C Likely benign same condition
DENND4B c.2439+10C>T Likely benign same condition
DENND4B c.3624-6C>T Likely benign same condition
DENND4B c.4115-3C>T Likely benign 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/dennd4b-p-pro230 (accessed [today's date]).

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