Is DENND5B p.Pro237Ser (c.709C>T) pathogenic?

DENND5B p.Pro237Ser (c.709C>T) is classified Uncertain significance in DENND5B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-13). AlphaMissense: likely pathogenic (0.8514); Absent from gnomAD v4.1.

How common is DENND5B p.Pro237Ser (c.709C>T) in the general population?

DENND5B p.Pro237Ser (c.709C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DENND5B p.Pro237Ser (c.709C>T)?

AlphaMissense predicts likely pathogenic (score 0.8514) — an in-silico prediction, not a clinical call.

DENND5B p.Pro237Ser

c.709C>T · rs1945986121 · VCV2284527

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8514 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8514	likely pathogenic
REVEL	0.331	indeterminate
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.92, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 164 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	27.3	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.Pro237Ser
Coding: c.709C>T
MANE Select: NM_144973
dbSNP: rs1945986121
Type: single nucleotide variant
Location: chr12:31479784 (GRCh38)
Gene constraint: LOEUF 0.351 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.12
Residue 237: the udenn domain

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

Similar variants

DENND5B p.Pro237His Uncertain significance ★ ⚠ same residue
DENND5B p.His852Tyr Pathogenic/Likely pathogenic ★★ ⚠ same type
DENND5B p.Glu381Lys Uncertain significance ★★ ⚠ same type
DENND5B p.Ile372Thr 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-pro237ser (accessed [today's date]).

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