Is AMZ1 p.Cys272Phe (c.815G>T) pathogenic?

AMZ1 p.Cys272Phe (c.815G>T) is classified Uncertain significance in AMZ1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-12). AlphaMissense: likely pathogenic (0.9513); Rare (popmax 0.133%, amr).

How common is AMZ1 p.Cys272Phe (c.815G>T) in the general population?

AMZ1 p.Cys272Phe (c.815G>T) is rare (popmax 0.133%, amr) (gnomAD).

What do computational predictors say about AMZ1 p.Cys272Phe (c.815G>T)?

AlphaMissense predicts likely pathogenic (score 0.9513) — an in-silico prediction, not a clinical call.

AMZ1 p.Cys272Phe

c.815G>T · VCV4640348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9513 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.133%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9513	likely pathogenic · top 3% in AMZ1
REVEL	0.743	pathogenic-leaning
SaProt	LLR -12.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.53	unconstrained · MANE · 12 kb · p 2.2e-43 · regional, not allelic
Overall
CADD	28.3	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 0.133% Admixed American · 80/59,984 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.101%

Overall 0.0447% 720/1,610,792 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.133%	750
Ashkenazi Jewishnot grpmax-eligible	0.0609%	1,643
European (non-Finnish)	0.049%	2,041
Remaining individualsnot grpmax-eligible	0.0466%	2,148
African / African-American	0.02%	5,000

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.Cys272Phe
Coding: c.815G>T
MANE Select: NM_001384743
Type: single nucleotide variant
Location: chr7:2709683 (GRCh38)
Gene constraint: LOEUF 1.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.62
Residue 272: a binding site

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-cys272phe (accessed [today's date]).

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