Is ATAD2 p.Arg380Leu (c.1139G>T) pathogenic?

ATAD2 p.Arg380Leu (c.1139G>T) is classified Uncertain significance in ATAD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely benign (0.2324); Very rare (popmax 8.48e-05%, nfe).

How common is ATAD2 p.Arg380Leu (c.1139G>T) in the general population?

ATAD2 p.Arg380Leu (c.1139G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ATAD2 p.Arg380Leu (c.1139G>T)?

AlphaMissense predicts likely benign (score 0.2324) — an in-silico prediction, not a clinical call.

ATAD2 p.Arg380Leu

c.1139G>T · VCV3958740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2324 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2324	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -8.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 11 kb · p 0.0021 · regional, not allelic
Overall
CADD	27.0	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 8.48e-05% European (non-Finnish) · 1/1,179,190 alleles

Overall 6.85e-05% 1/1,460,786 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: ATAD2
Protein: p.Arg380Leu
Coding: c.1139G>T
MANE Select: NM_014109
Type: single nucleotide variant
Location: chr8:123361557 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.63 · 120 PDB
Residue 380: the 'disordered' region

Full ATAD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATAD2 p.Arg380His Uncertain significance ★ ⚠ same residue
ATAD2 p.Ala1155Val Uncertain significance ★ ⚠ same type
ATAD2 p.Ala329Thr Uncertain significance ★ ⚠ same type
ATAD2 p.Ala338Ser Uncertain significance ★ ⚠ same type
ATAD2 p.Ala499Gly Uncertain significance ★ ⚠ same type
ATAD2 p.Ala644Gly Uncertain significance ★ ⚠ same type
ATAD2 p.Ala771Pro Uncertain significance ★ ⚠ same type
ATAD2 p.Ala81Val 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/atad2-p-arg380leu (accessed [today's date]).

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