Is AMZ1 p.Ala288Pro (c.862G>C) pathogenic?

AMZ1 p.Ala288Pro (c.862G>C) is classified Uncertain significance in AMZ1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely pathogenic (0.6711); Rare (popmax 0.117%, nfe).

How common is AMZ1 p.Ala288Pro (c.862G>C) in the general population?

AMZ1 p.Ala288Pro (c.862G>C) is rare (popmax 0.117%, nfe) (gnomAD).

What do computational predictors say about AMZ1 p.Ala288Pro (c.862G>C)?

AlphaMissense predicts likely pathogenic (score 0.6711) — an in-silico prediction, not a clinical call.

AMZ1 p.Ala288Pro

c.862G>C · rs139061616 · VCV2370752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6711 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6711	likely pathogenic
REVEL	0.306	indeterminate
SaProt	LLR -12.61	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 7.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.53	unconstrained · MANE · 12 kb · p 2.2e-43 · regional, not allelic
Overall
CADD	25.2	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 0.117% European (non-Finnish) · 1,380/1,179,878 alleles

Filtering AF 0.112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.11%

Overall 0.0979% 1,577/1,611,418 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.987%	101
Remaining individualsnot grpmax-eligible	0.124%	810
European (non-Finnish)grpmax	0.117%	855
Admixed American	0.0917%	1,091
Finnishnot grpmax-eligible	0.0365%	2,738
African / African-American	0.02%	5,000
South Asian	0.0187%	5,353
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,582

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AMZ1
Protein: p.Ala288Pro
Coding: c.862G>C
MANE Select: NM_001384743
dbSNP: rs139061616
Type: single nucleotide variant
Location: chr7:2709730 (GRCh38)
Gene constraint: LOEUF 1.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.62

Full AMZ1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMZ1 p.Arg481Ter Likely benign ★★ same type
AMZ1 p.Pro394Leu Likely benign ★★ same type
AMZ1 p.Ala122Pro Uncertain significance ★ ⚠ same type
AMZ1 p.Ala172Val Uncertain significance ★ ⚠ same type
AMZ1 p.Ala188Asp Uncertain significance ★ ⚠ same type
AMZ1 p.Ala208Ser Uncertain significance ★ ⚠ same type
AMZ1 p.Ala208Thr Uncertain significance ★ ⚠ same type
AMZ1 p.Ala230Val 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/amz1-p-ala288pro (accessed [today's date]).

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