Is AMZ1 p.Pro133Thr (c.397C>A) pathogenic?

AMZ1 p.Pro133Thr (c.397C>A) is classified Uncertain significance in AMZ1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). AlphaMissense: ambiguous (0.4431); Ultra-rare (popmax 0.0231%, afr).

How common is AMZ1 p.Pro133Thr (c.397C>A) in the general population?

AMZ1 p.Pro133Thr (c.397C>A) is ultra-rare (popmax 0.0231%, afr) (gnomAD).

What do computational predictors say about AMZ1 p.Pro133Thr (c.397C>A)?

AlphaMissense predicts ambiguous (score 0.4431) — an in-silico prediction, not a clinical call.

AMZ1 p.Pro133Thr

c.397C>A · VCV3537106

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4431 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4431	ambiguous
REVEL	0.281	benign-leaning
SaProt	LLR -10.02	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 6.5	GERP 0.96, phastCons 1
Regional constraint	o/e 1.53	unconstrained · MANE · 12 kb · p 2.2e-43 · regional, not allelic
Overall
CADD	23.5	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 0.0231% African / African-American · 17/73,454 alleles

Filtering AF 0.0147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00116% 18/1,554,178 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0231%	4,321
Admixed American	0.00189%	53,012

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.Pro133Thr
Coding: c.397C>A
MANE Select: NM_001384743
Type: single nucleotide variant
Location: chr7:2702814 (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.Pro133Leu Uncertain significance ★ ⚠ same residue
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

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-pro133thr (accessed [today's date]).

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