Is ADRM1 p.Pro280Leu (c.839C>T) pathogenic?

ADRM1 p.Pro280Leu (c.839C>T) is classified Uncertain significance in ADRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.0866); Ultra-rare (popmax 0.0201%, eas).

How common is ADRM1 p.Pro280Leu (c.839C>T) in the general population?

ADRM1 p.Pro280Leu (c.839C>T) is ultra-rare (popmax 0.0201%, eas) (gnomAD).

What do computational predictors say about ADRM1 p.Pro280Leu (c.839C>T)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

ADRM1 p.Pro280Leu

c.839C>T · rs752190888 · VCV3091134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -6.14	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 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 5,005 bp · p 0.0094 · regional, not allelic
Overall
CADD	21.1	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 0.0201% East Asian · 9/44,702 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00782%

Overall 0.00112% 18/1,608,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0201%	4,967
Remaining individualsnot grpmax-eligible	0.0145%	6,915

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: ADRM1
Protein: p.Pro280Leu
Coding: c.839C>T
MANE Select: NM_007002
dbSNP: rs752190888
Type: single nucleotide variant
Location: chr20:62307811 (GRCh38)
Gene constraint: LOEUF 0.188 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.34 · 21 PDB
Residue 280: the deubad domain; the 'interaction with uchl5' region

Full ADRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADRM1 p.Ala245= Benign ★★ same type
ADRM1 p.Ala324Val Benign ★★ same type
ADRM1 p.Asp266= Benign ★★ same type
ADRM1 p.Pro315= Benign ★★ same type
ADRM1 p.Ala149Gly Uncertain significance ★ ⚠ same type
ADRM1 p.Ala236Thr Uncertain significance ★ ⚠ same type
ADRM1 p.Ala239Thr Uncertain significance ★ ⚠ same type
ADRM1 p.Ala245Thr 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/adrm1-p-pro280leu (accessed [today's date]).

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