Is DENND6A p.Pro202Ser (c.604C>T) pathogenic?

DENND6A p.Pro202Ser (c.604C>T) is classified Uncertain significance in DENND6A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.1528); Very rare (popmax 0.00299%, nfe).

How common is DENND6A p.Pro202Ser (c.604C>T) in the general population?

DENND6A p.Pro202Ser (c.604C>T) is very rare (popmax 0.00299%, nfe) (gnomAD).

What do computational predictors say about DENND6A p.Pro202Ser (c.604C>T)?

AlphaMissense predicts likely benign (score 0.1528) — an in-silico prediction, not a clinical call.

DENND6A p.Pro202Ser

c.604C>T · rs764580298 · VCV2604583

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1528 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00299%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1528	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -8.81	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 8.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 65 kb · p 1e-12 · regional, not allelic
Overall
CADD	23.4	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 0.00299% European (non-Finnish) · 35/1,168,814 alleles

Filtering AF 0.00217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00192%

Overall 0.00223% 35/1,570,146 alleles · very rare

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: DENND6A
Protein: p.Pro202Ser
Coding: c.604C>T
MANE Select: NM_152678
dbSNP: rs764580298
Type: single nucleotide variant
Location: chr3:57661461 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.94
Residue 202: the udenn domain

Full DENND6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DENND6A p.Ala207Val Uncertain significance ★ ⚠ same type
DENND6A p.Ala35Ser Uncertain significance ★ ⚠ same type
DENND6A p.Ala35Val Uncertain significance ★ ⚠ same type
DENND6A p.Arg235Trp Uncertain significance ★ ⚠ same type
DENND6A p.Arg27Ser Uncertain significance ★ ⚠ same type
DENND6A p.Arg370Leu Uncertain significance ★ ⚠ same type
DENND6A p.Arg506Trp Uncertain significance ★ ⚠ same type
DENND6A p.Arg521Gln 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/dennd6a-p-pro202ser (accessed [today's date]).

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