Is AMZ1 p.Arg93Trp (c.277C>T) pathogenic?

AMZ1 p.Arg93Trp (c.277C>T) is classified Uncertain significance in AMZ1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). AlphaMissense: likely benign (0.1399); Ultra-rare (popmax 0.0209%, sas).

How common is AMZ1 p.Arg93Trp (c.277C>T) in the general population?

AMZ1 p.Arg93Trp (c.277C>T) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about AMZ1 p.Arg93Trp (c.277C>T)?

AlphaMissense predicts likely benign (score 0.1399) — an in-silico prediction, not a clinical call.

AMZ1 p.Arg93Trp

c.277C>T · VCV4048348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1399 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1399	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.91, phastCons 0.4
Regional constraint	o/e 1.53	unconstrained · MANE · 12 kb · p 2.2e-43 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0209% South Asian · 19/91,072 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00217% 35/1,612,974 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,793
African / African-American	0.00799%	12,508
Admixed American	0.00167%	60,016
Finnishnot grpmax-eligible	0.00159%	62,892
European (non-Finnish)	0.000678%	147,502

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.Arg93Trp
Coding: c.277C>T
MANE Select: NM_001384743
Type: single nucleotide variant
Location: chr7:2700728 (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-arg93trp (accessed [today's date]).

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