Is ADGRA3 p.Ala541Ser (c.1621G>T) pathogenic?

ADGRA3 p.Ala541Ser (c.1621G>T) is classified Uncertain significance in ADGRA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-10). AlphaMissense: ambiguous (0.4395); Very rare (popmax 0.00229%, nfe).

How common is ADGRA3 p.Ala541Ser (c.1621G>T) in the general population?

ADGRA3 p.Ala541Ser (c.1621G>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about ADGRA3 p.Ala541Ser (c.1621G>T)?

AlphaMissense predicts ambiguous (score 0.4395) — an in-silico prediction, not a clinical call.

ADGRA3 p.Ala541Ser

c.1621G>T · rs759273052 · VCV1008284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4395	ambiguous
REVEL	0.29	benign-leaning
SaProt	LLR -10.57	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.48	acceptor gain · deltas
Pangolin	Δ0.31	gain · loss 0.29 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 48 kb · p 0.57 · regional, not allelic
Overall
CADD	27.4	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 0.00229% European (non-Finnish) · 27/1,179,712 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00174% 28/1,613,470 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,693
African / African-American	0.00134%	74,846

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.Ala541Ser
Coding: c.1621G>T
MANE Select: NM_145290
dbSNP: rs759273052
Type: single nucleotide variant
Location: chr4:22421074 (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.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
ADGRA3 p.Ala407Thr 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-ala541ser (accessed [today's date]).

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