Is DENND6A p.Pro264Arg (c.791C>G) pathogenic?

DENND6A p.Pro264Arg (c.791C>G) is classified Uncertain significance in DENND6A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: ambiguous (0.389); Very rare (popmax 0.00885%, amr).

How common is DENND6A p.Pro264Arg (c.791C>G) in the general population?

DENND6A p.Pro264Arg (c.791C>G) is very rare (popmax 0.00885%, amr) (gnomAD).

What do computational predictors say about DENND6A p.Pro264Arg (c.791C>G)?

AlphaMissense predicts ambiguous (score 0.389) — an in-silico prediction, not a clinical call.

DENND6A p.Pro264Arg

c.791C>G · rs746610495 · VCV3081693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.389 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00885%, amr)

Computational evidence

Protein change
AlphaMissense	0.389	ambiguous
REVEL	0.49	indeterminate
SaProt	LLR -10.80	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 65 kb · p 1e-12 · regional, not allelic
Overall
CADD	28.2	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

Grpmax group 0.00885% Admixed American · 5/56,468 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00218%

Overall 0.000698% 11/1,575,044 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00885%	11,294
Remaining individualsnot grpmax-eligible	0.00165%	60,706
African / African-American	0.00136%	73,326
European (non-Finnish)	0.000346%	289,070

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.Pro264Arg
Coding: c.791C>G
MANE Select: NM_152678
dbSNP: rs746610495
Type: single nucleotide variant
Location: chr3:57657707 (GRCh38)
Gene constraint: LOEUF 0.708 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.94

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-pro264arg (accessed [today's date]).

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