Is ADGRA3 p.Pro237Leu (c.710C>T) pathogenic?

ADGRA3 p.Pro237Leu (c.710C>T) is classified Uncertain significance in ADGRA3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-03). AlphaMissense: likely benign (0.1267); Ultra-rare (popmax 0.02%, afr).

How common is ADGRA3 p.Pro237Leu (c.710C>T) in the general population?

ADGRA3 p.Pro237Leu (c.710C>T) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about ADGRA3 p.Pro237Leu (c.710C>T)?

AlphaMissense predicts likely benign (score 0.1267) — an in-silico prediction, not a clinical call.

ADGRA3 p.Pro237Leu

c.710C>T · rs560712931 · VCV1036500

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1267 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1267	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -5.51	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 80 kb · p 9.9e-07 · regional, not allelic
Overall
CADD	22.8	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 0.02% African / African-American · 15/74,924 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.0018% 29/1,610,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,995
Admixed American	0.0117%	8,559
European (non-Finnish)	0.000595%	168,075

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.Pro237Leu
Coding: c.710C>T
MANE Select: NM_145290
dbSNP: rs560712931
Type: single nucleotide variant
Location: chr4:22442860 (GRCh38)
Gene constraint: LOEUF 0.607 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.20
Residue 237: the lrrct domain

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

Similar variants

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ADGRA3 p.Ala177Val Uncertain significance ★★ ⚠ same type
ADGRA3 p.Ala26Pro Uncertain significance ★★ ⚠ same type
ADGRA3 p.Ala316Pro Uncertain significance ★★ ⚠ same type
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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-pro237leu (accessed [today's date]).

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