Is AMZ2 p.His331Arg (c.992A>G) pathogenic?

AMZ2 p.His331Arg (c.992A>G) is classified Benign in AMZ2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-28). AlphaMissense: likely benign (0.0453); Low-frequency (popmax 4.86%, afr); Associated with AMZ2-related disorder.

What condition is associated with AMZ2 p.His331Arg (c.992A>G)?

AMZ2 p.His331Arg (c.992A>G) is associated with AMZ2-related disorder (ClinVar).

How common is AMZ2 p.His331Arg (c.992A>G) in the general population?

AMZ2 p.His331Arg (c.992A>G) is low-frequency (popmax 4.86%, afr) (gnomAD).

What do computational predictors say about AMZ2 p.His331Arg (c.992A>G)?

AlphaMissense predicts likely benign (score 0.0453) — an in-silico prediction, not a clinical call.

AMZ2 p.His331Arg

c.992A>G · rs113287202 · VCV3039332

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0453 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.86%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AMZ2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0453	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.01	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 -1.3	GERP -2.3
Regional constraint	o/e 0.92	unconstrained · MANE · 6,778 bp · p 0.078 · regional, not allelic
Overall
CADD	0.411	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 4.86% African / African-American · 3,645/75,044 alleles

Filtering AF 4.73% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.67%

Overall 0.268% 4,320/1,614,206 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.86%	21
Remaining individualsnot grpmax-eligible	0.422%	237
Admixed American	0.408%	245
Middle Eastern	0.248%	404
South Asian	0.0209%	4,794
European (non-Finnish)	0.0111%	9,008
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602

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.His331Arg
Coding: c.992A>G
MANE Select: NM_016627
dbSNP: rs113287202
Type: single nucleotide variant
Location: chr17:68256878 (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

Disease context

AMZ2-related disorder

Similar variants

AMZ2 c.586+8G>A Likely benign same condition
AMZ2 p.Ala356= Benign same condition
AMZ2 p.Asn30Asp Benign same condition
AMZ2 p.Gly153= Likely benign same condition
AMZ2 p.Gly198= Benign same condition
AMZ2 p.Ile256= Likely benign same condition
AMZ2 p.Ala117Thr Uncertain significance ★ ⚠ same type
AMZ2 p.Ala269Val 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-his331arg (accessed [today's date]).

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