Is DENND5B p.Phe654Cys (c.1961T>G) pathogenic?

DENND5B p.Phe654Cys (c.1961T>G) is classified Uncertain significance in DENND5B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-08). AlphaMissense: ambiguous (0.4719); Absent from gnomAD v4.1.

How common is DENND5B p.Phe654Cys (c.1961T>G) in the general population?

DENND5B p.Phe654Cys (c.1961T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND5B p.Phe654Cys (c.1961T>G)?

AlphaMissense predicts ambiguous (score 0.4719) — an in-silico prediction, not a clinical call.

DENND5B p.Phe654Cys

c.1961T>G · rs2498962480 · VCV2305599

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4719 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4719	ambiguous
REVEL	0.519	indeterminate
SaProt	LLR -7.00	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 164 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	27.7	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: DENND5B
Protein: p.Phe654Cys
Coding: c.1961T>G
MANE Select: NM_144973
dbSNP: rs2498962480
Type: single nucleotide variant
Location: chr12:31442826 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.12

Full DENND5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DENND5B p.His852Tyr Pathogenic/Likely pathogenic ★★ ⚠ same type
DENND5B p.Glu381Lys Uncertain significance ★★ ⚠ same type
DENND5B p.Ile372Thr Uncertain significance ★★ ⚠ same type
DENND5B p.Pro237Ser Uncertain significance ★★ ⚠ same type
DENND5B p.Val26Met Uncertain significance ★★ ⚠ same type
DENND5B p.Glu774Gly Pathogenic ★ ⚠ same type
DENND5B c.128-3722A>C Uncertain significance ★ same type
DENND5B c.1861+2T>A 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/dennd5b-p-phe654cys (accessed [today's date]).

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