Is ADRA1D p.Pro457Leu (c.1370C>T) pathogenic?

ADRA1D p.Pro457Leu (c.1370C>T) is classified Uncertain significance in ADRA1D (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-09). AlphaMissense: likely benign (0.0709); Very rare (popmax 0.000268%, nfe).

How common is ADRA1D p.Pro457Leu (c.1370C>T) in the general population?

ADRA1D p.Pro457Leu (c.1370C>T) is very rare (popmax 0.000268%, nfe) (gnomAD).

What do computational predictors say about ADRA1D p.Pro457Leu (c.1370C>T)?

AlphaMissense predicts likely benign (score 0.0709) — an in-silico prediction, not a clinical call.

ADRA1D p.Pro457Leu

c.1370C>T · rs1008725026 · VCV2288067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000268%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0709	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -6.99	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 0.19	GERP -2.7
Regional constraint	o/e 1.00	unconstrained · MANE · 27 kb · p 0.98 · regional, not allelic
Overall
CADD	12.38	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 0.000268% European (non-Finnish) · 3/1,117,504 alleles

Filtering AF 7.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000205% 3/1,465,606 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: ADRA1D
Protein: p.Pro457Leu
Coding: c.1370C>T
MANE Select: NM_000678
dbSNP: rs1008725026
Type: single nucleotide variant
Location: chr20:4221872 (GRCh38)
Gene constraint: LOEUF 1.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.88
Residue 457: the 'disordered' region

Full ADRA1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADRA1D p.Pro457Arg Uncertain significance ★ ⚠ same residue
ADRA1D p.Ala174Val Uncertain significance ★ ⚠ same type
ADRA1D p.Ala20Gly Uncertain significance ★ ⚠ same type
ADRA1D p.Ala20Thr Uncertain significance ★ ⚠ same type
ADRA1D p.Ala218Val Uncertain significance ★ ⚠ same type
ADRA1D p.Ala255Pro Uncertain significance ★ ⚠ same type
ADRA1D p.Ala35Gly Uncertain significance ★ ⚠ same type
ADRA1D p.Ala36Gly 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/adra1d-p-pro457leu (accessed [today's date]).

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