Is ADGRL2 p.Ile421Val (c.1261A>G) pathogenic?

ADGRL2 p.Ile421Val (c.1261A>G) is classified Uncertain significance in ADGRL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely benign (0.0615); Ultra-rare (popmax 0.0117%, amr).

How common is ADGRL2 p.Ile421Val (c.1261A>G) in the general population?

ADGRL2 p.Ile421Val (c.1261A>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about ADGRL2 p.Ile421Val (c.1261A>G)?

AlphaMissense predicts likely benign (score 0.0615) — an in-silico prediction, not a clinical call.

ADGRL2 p.Ile421Val

c.1261A>G · VCV3272274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0615 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0615	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -5.87	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 9.4	GERP 5.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 16 kb · p 0.65 · regional, not allelic
Overall
CADD	21.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I417V vs ClinVar I421V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/59,988 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.0026% 42/1,613,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,570
European (non-Finnish)	0.0028%	35,757
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00133%	74,928

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: ADGRL2
Protein: p.Ile421Val
Coding: c.1261A>G
MANE Select: NM_001366006
Type: single nucleotide variant
Location: chr1:81950239 (GRCh38)
Gene constraint: LOEUF 0.301 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.66 · 1 PDB

Full ADGRL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRL2 p.Lys555Arg Likely benign ★★ same type
ADGRL2 p.Thr1294= Benign ★★ same type
ADGRL2 p.Ala1070Thr Uncertain significance ★ ⚠ same type
ADGRL2 p.Ala1090Val Uncertain significance ★ ⚠ same type
ADGRL2 p.Ala160Val Uncertain significance ★ ⚠ same type
ADGRL2 p.Ala170Val Uncertain significance ★ ⚠ same type
ADGRL2 p.Ala191Ser Uncertain significance ★ ⚠ same type
ADGRL2 p.Ala29Val 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/adgrl2-p-ile421val (accessed [today's date]).

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