Is AZGP1 p.Asp274Val (c.821A>T) pathogenic?

AZGP1 p.Asp274Val (c.821A>T) is classified Uncertain significance in AZGP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: ambiguous (0.39); Very rare (popmax 0.00898%, nfe).

How common is AZGP1 p.Asp274Val (c.821A>T) in the general population?

AZGP1 p.Asp274Val (c.821A>T) is very rare (popmax 0.00898%, nfe) (gnomAD).

What do computational predictors say about AZGP1 p.Asp274Val (c.821A>T)?

AlphaMissense predicts ambiguous (score 0.39) — an in-silico prediction, not a clinical call.

AZGP1 p.Asp274Val

c.821A>T · rs376472652 · VCV2206141

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.39 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00898%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.39	ambiguous
REVEL	0.06	moderately benign-leaning
SaProt	LLR -11.39	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 0.84	GERP 0.76, phastCons 0.017
Regional constraint	o/e 0.97	unconstrained · MANE · 9,014 bp · p 0.57 · regional, not allelic
Overall
CADD	18.19	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 0.00898% European (non-Finnish) · 106/1,180,042 alleles

Filtering AF 0.00757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00706%

Overall 0.00669% 108/1,614,030 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00898%	11,132
Remaining individualsnot grpmax-eligible	0.0032%	31,245

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.Asp274Val
Coding: c.821A>T
MANE Select: NM_001185
dbSNP: rs376472652
Type: single nucleotide variant
Location: chr7:99967079 (GRCh38)
Gene constraint: LOEUF 1.141 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.26 · 10 PDB
Residue 274: the ig-like c1-type domain; a disulfide bond

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-asp274val (accessed [today's date]).

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