Is ADGRA3 p.Leu70Phe (c.208C>T) pathogenic?

ADGRA3 p.Leu70Phe (c.208C>T) is classified Uncertain significance in ADGRA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: ambiguous (0.4148); Very rare (popmax 0.00135%, afr).

How common is ADGRA3 p.Leu70Phe (c.208C>T) in the general population?

ADGRA3 p.Leu70Phe (c.208C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about ADGRA3 p.Leu70Phe (c.208C>T)?

AlphaMissense predicts ambiguous (score 0.4148) — an in-silico prediction, not a clinical call.

ADGRA3 p.Leu70Phe

c.208C>T · VCV3647357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4148	ambiguous
REVEL	0.222	benign-leaning
SaProt	LLR -11.71	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 0.39, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 80 kb · p 9.9e-07 · regional, not allelic
Overall
CADD	25.6	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 0.00135% African / African-American · 1/73,996 alleles

Overall 6.89e-05% 1/1,450,480 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: ADGRA3
Protein: p.Leu70Phe
Coding: c.208C>T
MANE Select: NM_145290
Type: single nucleotide variant
Location: chr4:22515577 (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.Leu70= Likely benign ★ 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-leu70phe (accessed [today's date]).

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