Is ADGRB1 p.Arg464Trp (c.1390C>T) pathogenic?

ADGRB1 p.Arg464Trp (c.1390C>T) is classified Uncertain significance in ADGRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-08). AlphaMissense: ambiguous (0.3667); Very rare (popmax 0.00595%, nfe).

How common is ADGRB1 p.Arg464Trp (c.1390C>T) in the general population?

ADGRB1 p.Arg464Trp (c.1390C>T) is very rare (popmax 0.00595%, nfe) (gnomAD).

What do computational predictors say about ADGRB1 p.Arg464Trp (c.1390C>T)?

AlphaMissense predicts ambiguous (score 0.3667) — an in-silico prediction, not a clinical call.

ADGRB1 p.Arg464Trp

c.1390C>T · VCV3835094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3667 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00595%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3667	ambiguous
REVEL	0.205	benign-leaning
SaProt	LLR -9.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.3	GERP 0.2, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 13 kb · p 4e-22 · regional, not allelic
Overall
CADD	29.5	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 0.00595% European (non-Finnish) · 70/1,175,656 alleles

Filtering AF 0.0048% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0044%

Overall 0.00474% 76/1,602,906 alleles · very rare exomes 74/1,450,772 · genomes 2/152,134 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00595%	16,795
Admixed American	0.00342%	29,239
Remaining individualsnot grpmax-eligible	0.00322%	31,022
South Asian	0.00225%	44,510

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: ADGRB1
Protein: p.Arg464Trp
Coding: c.1390C>T
MANE Select: NM_001702
Type: single nucleotide variant
Location: chr8:142478189 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.83

Full ADGRB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRB1 c.2130+15C>G Benign ★★ same type
ADGRB1 p.Ala1507Val Benign ★★ same type
ADGRB1 p.Pro1295= Benign ★★ same type
ADGRB1 p.Pro575= Benign ★★ same type
ADGRB1 p.Ser480= Benign ★★ same type
ADGRB1 p.Thr1274= Benign ★★ same type
ADGRB1 p.Ala131Thr Uncertain significance ★ ⚠ same type
ADGRB1 p.Ala1406Gly 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/adgrb1-p-arg464trp (accessed [today's date]).

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