Is ADGRA3 p.Arg413His (c.1238G>A) pathogenic?

ADGRA3 p.Arg413His (c.1238G>A) is classified Uncertain significance in ADGRA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). AlphaMissense: likely benign (0.0793); Very rare (popmax 0.00263%, nfe).

How common is ADGRA3 p.Arg413His (c.1238G>A) in the general population?

ADGRA3 p.Arg413His (c.1238G>A) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about ADGRA3 p.Arg413His (c.1238G>A)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

ADGRA3 p.Arg413His

c.1238G>A · VCV4737307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	26.3	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 0.00263% European (non-Finnish) · 31/1,179,824 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00217% 35/1,612,356 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00263%	38,059
East Asian	0.00223%	44,872
Admixed American	0.00167%	59,974
Remaining individualsnot grpmax-eligible	0.0016%	62,342
African / African-American	0.00134%	74,814

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.Arg413His
Coding: c.1238G>A
MANE Select: NM_145290
Type: single nucleotide variant
Location: chr4:22436489 (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.Arg413Cys 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
ADGRA3 p.Ala37Gly 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-arg413his (accessed [today's date]).

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