Is ADGRA2 p.Phe430Leu (c.1288T>C) pathogenic?

ADGRA2 p.Phe430Leu (c.1288T>C) is classified Uncertain significance in ADGRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.9915); Very rare (popmax 0.000509%, nfe).

How common is ADGRA2 p.Phe430Leu (c.1288T>C) in the general population?

ADGRA2 p.Phe430Leu (c.1288T>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about ADGRA2 p.Phe430Leu (c.1288T>C)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

ADGRA2 p.Phe430Leu

c.1288T>C · VCV4638104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic · top 2% in ADGRA2
REVEL	0.142	moderately benign-leaning
SaProt	LLR -4.16	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.0006 · regional, not allelic
Overall
CADD	22.4	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 0.000509% European (non-Finnish) · 6/1,178,384 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000373% 6/1,610,076 alleles · very rare

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.Phe430Leu
Coding: c.1288T>C
MANE Select: NM_032777
Type: single nucleotide variant
Location: chr8:37833200 (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-phe430leu (accessed [today's date]).

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