Is AZGP1 p.Leu89Pro (c.266T>C) pathogenic?

AZGP1 p.Leu89Pro (c.266T>C) is classified Uncertain significance in AZGP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-08). AlphaMissense: likely pathogenic (0.8956); Very rare (popmax 0.00401%, afr).

How common is AZGP1 p.Leu89Pro (c.266T>C) in the general population?

AZGP1 p.Leu89Pro (c.266T>C) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about AZGP1 p.Leu89Pro (c.266T>C)?

AlphaMissense predicts likely pathogenic (score 0.8956) — an in-silico prediction, not a clinical call.

AZGP1 p.Leu89Pro

c.266T>C · rs372180028 · VCV3132498

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8956	likely pathogenic · top 7% in AZGP1
REVEL	0.526	indeterminate
SaProt	LLR -13.08	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.93	GERP 0.59
Regional constraint	o/e 0.97	unconstrained · MANE · 9,014 bp · p 0.57 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00401% African / African-American · 3/74,884 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,958 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,961
European (non-Finnish)	8.47e-05%	1,180,008

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: AZGP1
Protein: p.Leu89Pro
Coding: c.266T>C
MANE Select: NM_001185
dbSNP: rs372180028
Type: single nucleotide variant
Location: chr7:99971817 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.26 · 10 PDB
Residue 89: an α-helix

Full AZGP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AZGP1 p.Ala133Thr Uncertain significance ★ ⚠ same type
AZGP1 p.Ala161Asp Uncertain significance ★ ⚠ same type
AZGP1 p.Ala188Val Uncertain significance ★ ⚠ same type
AZGP1 p.Ala18Thr Uncertain significance ★ ⚠ same type
AZGP1 p.Ala276Asp Uncertain significance ★ ⚠ same type
AZGP1 p.Ala276Ser Uncertain significance ★ ⚠ same type
AZGP1 p.Ala276Val Uncertain significance ★ ⚠ same type
AZGP1 p.Arg120Trp 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/azgp1-p-leu89pro (accessed [today's date]).

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