Is ADGRA2 p.Arg100Cys (c.298C>T) pathogenic?

ADGRA2 p.Arg100Cys (c.298C>T) is classified Uncertain significance in ADGRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.2523); Ultra-rare (popmax 0.0362%, sas).

How common is ADGRA2 p.Arg100Cys (c.298C>T) in the general population?

ADGRA2 p.Arg100Cys (c.298C>T) is ultra-rare (popmax 0.0362%, sas) (gnomAD).

What do computational predictors say about ADGRA2 p.Arg100Cys (c.298C>T)?

AlphaMissense predicts likely benign (score 0.2523) — an in-silico prediction, not a clinical call.

ADGRA2 p.Arg100Cys

c.298C>T · rs267601911 · VCV4638096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2523 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0362%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2523	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -11.32	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.0006 · regional, not allelic
Overall
CADD	29.4	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 0.0362% South Asian · 33/91,058 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0231%

Overall 0.00304% 49/1,613,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0362%	2,759
Middle Eastern	0.0329%	3,041
Admixed American	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0032%	31,230
African / African-American	0.00267%	37,451
European (non-Finnish)	0.000678%	147,395

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.Arg100Cys
Coding: c.298C>T
MANE Select: NM_032777
dbSNP: rs267601911
Type: single nucleotide variant
Location: chr8:37814927 (GRCh38)
Gene constraint: LOEUF 0.943 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.47

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-arg100cys (accessed [today's date]).

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