Is DENND4B p.Val90Ile (c.268G>A) pathogenic?

DENND4B p.Val90Ile (c.268G>A) is classified Uncertain significance in DENND4B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-09). AlphaMissense: likely benign (0.082); Ultra-rare (popmax 0.0816%, afr).

How common is DENND4B p.Val90Ile (c.268G>A) in the general population?

DENND4B p.Val90Ile (c.268G>A) is ultra-rare (popmax 0.0816%, afr) (gnomAD).

What do computational predictors say about DENND4B p.Val90Ile (c.268G>A)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

DENND4B p.Val90Ile

c.268G>A · rs200116588 · VCV2511012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0816%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -6.98	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 1.4	phastCons 0.8
Regional constraint	o/e 0.71	unconstrained · MANE · 9,410 bp · p 1.8e-22 · regional, not allelic
Overall
CADD	22.1	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0816% African / African-American · 61/74,782 alleles

Filtering AF 0.0651% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0592%

Overall 0.0119% 191/1,603,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.243%	412
African / African-Americangrpmax	0.0816%	1,226
Remaining individualsnot grpmax-eligible	0.0226%	4,430
Middle Eastern	0.0167%	6,004
Admixed American	0.0136%	7,338
East Asian	0.00674%	14,844
South Asian	0.00334%	29,974
Finnishnot grpmax-eligible	0.00314%	31,823
European (non-Finnish)	0.00247%	40,499

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val90Ile
Coding: c.268G>A
MANE Select: NM_014856
dbSNP: rs200116588
Type: single nucleotide variant
Location: chr1:153944107 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.32
Residue 90: the mabp domain

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

Similar variants

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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
DENND4B p.Ala275Thr 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-val90ile (accessed [today's date]).

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