Is AMZ2 p.Pro131Ala (c.391C>G) pathogenic?

AMZ2 p.Pro131Ala (c.391C>G) is classified Uncertain significance in AMZ2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0802); Very rare (popmax 0.00402%, afr).

How common is AMZ2 p.Pro131Ala (c.391C>G) in the general population?

AMZ2 p.Pro131Ala (c.391C>G) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about AMZ2 p.Pro131Ala (c.391C>G)?

AlphaMissense predicts likely benign (score 0.0802) — an in-silico prediction, not a clinical call.

AMZ2 p.Pro131Ala

c.391C>G · VCV4640368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0802 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0802	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -8.68	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 0.39	GERP -1.4, phastCons 0.037
Regional constraint	o/e 0.92	unconstrained · MANE · 6,778 bp · p 0.078 · regional, not allelic
Overall
CADD	15.53	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 0.00402% African / African-American · 3/74,704 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000186% 3/1,610,486 alleles · very rare

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: AMZ2
Protein: p.Pro131Ala
Coding: c.391C>G
MANE Select: NM_016627
Type: single nucleotide variant
Location: chr17:68250901 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.55

Full AMZ2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMZ2 p.Ala117Thr Uncertain significance ★ ⚠ same type
AMZ2 p.Ala269Val Uncertain significance ★ ⚠ same type
AMZ2 p.Arg101Lys Uncertain significance ★ ⚠ same type
AMZ2 p.Arg247Gln Uncertain significance ★ ⚠ same type
AMZ2 p.Arg263Gln Uncertain significance ★ ⚠ same type
AMZ2 p.Arg283Trp Uncertain significance ★ ⚠ same type
AMZ2 p.Arg284Pro Uncertain significance ★ ⚠ same type
AMZ2 p.Arg35Cys 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/amz2-p-pro131ala (accessed [today's date]).

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