Is ADGRA3 p.Arg378Gln (c.1133G>A) pathogenic?

ADGRA3 p.Arg378Gln (c.1133G>A) is classified Uncertain significance in ADGRA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.135); Ultra-rare (popmax 0.0758%, sas).

How common is ADGRA3 p.Arg378Gln (c.1133G>A) in the general population?

ADGRA3 p.Arg378Gln (c.1133G>A) is ultra-rare (popmax 0.0758%, sas) (gnomAD).

What do computational predictors say about ADGRA3 p.Arg378Gln (c.1133G>A)?

AlphaMissense predicts likely benign (score 0.135) — an in-silico prediction, not a clinical call.

ADGRA3 p.Arg378Gln

c.1133G>A · rs535789557 · VCV962703

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.135 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0758%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.135	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -6.06	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 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 80 kb · p 9.9e-07 · regional, not allelic
Overall
CADD	24.2	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 0.0758% South Asian · 69/91,082 alleles

Filtering AF 0.0613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0561%

Overall 0.00663% 107/1,614,028 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0758%	1,320
Middle Eastern	0.0165%	6,050
Admixed American	0.015%	6,668
Remaining individualsnot grpmax-eligible	0.0128%	7,813
African / African-American	0.008%	12,503
East Asian	0.00669%	14,951
European (non-Finnish)	0.000932%	107,272

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: ADGRA3
Protein: p.Arg378Gln
Coding: c.1133G>A
MANE Select: NM_145290
dbSNP: rs535789557
Type: single nucleotide variant
Location: chr4:22436594 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.20

Full ADGRA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRA3 p.Arg378Trp Uncertain significance ★★ ⚠ same residue
ADGRA3 p.Arg378Leu Uncertain significance ★ ⚠ same residue
ADGRA3 p.Ala1008Val Uncertain significance ★★ ⚠ same type
ADGRA3 p.Ala1120Val Uncertain significance ★★ ⚠ same type
ADGRA3 p.Ala1127Ser Uncertain significance ★★ ⚠ same type
ADGRA3 p.Ala177Val Uncertain significance ★★ ⚠ same type
ADGRA3 p.Ala26Pro Uncertain significance ★★ ⚠ same type
ADGRA3 p.Ala316Pro 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/adgra3-p-arg378gln (accessed [today's date]).

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