Is ADGRA2 p.Trp702Arg (c.2104T>C) pathogenic?

ADGRA2 p.Trp702Arg (c.2104T>C) is classified Uncertain significance in ADGRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: ambiguous (0.3562); Rare (popmax 0.268%, mid).

How common is ADGRA2 p.Trp702Arg (c.2104T>C) in the general population?

ADGRA2 p.Trp702Arg (c.2104T>C) is rare (popmax 0.268%, mid) (gnomAD).

What do computational predictors say about ADGRA2 p.Trp702Arg (c.2104T>C)?

AlphaMissense predicts ambiguous (score 0.3562) — an in-silico prediction, not a clinical call.

ADGRA2 p.Trp702Arg

c.2104T>C · rs375163748 · VCV2359756

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3562 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.268%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3562	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -5.87	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.0006 · regional, not allelic
Overall
CADD	22.8	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 0.268% Middle Eastern · 16/5,970 alleles

Filtering AF 0.168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.011% 171/1,551,032 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.268%	373
Admixed American	0.0529%	1,891
South Asian	0.031%	3,230
Remaining individualsnot grpmax-eligible	0.0283%	3,536
Finnishnot grpmax-eligible	0.0119%	8,421
Ashkenazi Jewishnot grpmax-eligible	0.00702%	14,246
European (non-Finnish)	0.00662%	15,095

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: ADGRA2
Protein: p.Trp702Arg
Coding: c.2104T>C
MANE Select: NM_032777
dbSNP: rs375163748
Type: single nucleotide variant
Location: chr8:37837784 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.47
Residue 702: the gain-b domain

Full ADGRA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRA2 c.1608+5T>C Benign ★★ same type
ADGRA2 p.Ala681Thr Benign ★★ ⚠ same type
ADGRA2 p.Arg671= Benign ★★ same type
ADGRA2 p.Ala1082Ser Uncertain significance ★ ⚠ same type
ADGRA2 p.Ala1094Ser Uncertain significance ★ ⚠ same type
ADGRA2 p.Ala1098Val Uncertain significance ★ ⚠ same type
ADGRA2 p.Ala1102Thr Uncertain significance ★ ⚠ same type
ADGRA2 p.Ala1102Val 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/adgra2-p-trp702arg (accessed [today's date]).

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