Is ADGB p.Pro519Ser (c.1555C>T) pathogenic?

ADGB p.Pro519Ser (c.1555C>T) is classified Uncertain significance in ADGB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely benign (0.1491); Ultra-rare (popmax 0.0204%, nfe).

How common is ADGB p.Pro519Ser (c.1555C>T) in the general population?

ADGB p.Pro519Ser (c.1555C>T) is ultra-rare (popmax 0.0204%, nfe) (gnomAD).

What do computational predictors say about ADGB p.Pro519Ser (c.1555C>T)?

AlphaMissense predicts likely benign (score 0.1491) — an in-silico prediction, not a clinical call.

ADGB p.Pro519Ser

c.1555C>T · VCV3495646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1491 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0204%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1491	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -6.12	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 2.7	GERP 0.81, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 216 kb · p 0.17 · regional, not allelic
Overall
CADD	18.48	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 0.0204% European (non-Finnish) · 231/1,129,620 alleles

Filtering AF 0.0183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0174%

Overall 0.0155% 237/1,528,488 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0204%	4,890
Remaining individualsnot grpmax-eligible	0.00674%	14,837
African / African-American	0.00138%	72,324
South Asian	0.00121%	82,314

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: ADGB
Protein: p.Pro519Ser
Coding: c.1555C>T
MANE Select: NM_024694
Type: single nucleotide variant
Location: chr6:146692893 (GRCh38)
Gene constraint: LOEUF 0.941 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.79

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

Similar variants

ADGB p.Pro519Leu Uncertain significance ★ ⚠ same residue
ADGB p.Ile645= Likely benign ★★ same type
ADGB p.Ala1104Asp Uncertain significance ★ ⚠ same type
ADGB p.Ala1104Gly Uncertain significance ★ ⚠ same type
ADGB p.Ala1339Val Uncertain significance ★ ⚠ same type
ADGB p.Ala1443Glu Uncertain significance ★ ⚠ same type
ADGB p.Ala145Glu Uncertain significance ★ ⚠ same type
ADGB p.Ala1567Glu 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/adgb-p-pro519ser (accessed [today's date]).

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