Is AMY2B p.Arg282Cys (c.844C>T) pathogenic?

AMY2B p.Arg282Cys (c.844C>T) is classified Uncertain significance in AMY2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). AlphaMissense: likely pathogenic (0.6364); Very rare (popmax 0.00669%, eas).

How common is AMY2B p.Arg282Cys (c.844C>T) in the general population?

AMY2B p.Arg282Cys (c.844C>T) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about AMY2B p.Arg282Cys (c.844C>T)?

AlphaMissense predicts likely pathogenic (score 0.6364) — an in-silico prediction, not a clinical call.

AMY2B p.Arg282Cys

c.844C>T · rs368462934 · VCV2360218

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6364	likely pathogenic
REVEL	0.75	pathogenic-leaning
SaProt	LLR -15.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.72, phastCons 0.92
Regional constraint	o/e 1.01	unconstrained · MANE · 7,894 bp · p 0.74 · regional, not allelic
Overall
CADD	26.9	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 0.00669% East Asian · 3/44,858 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00366% 59/1,611,262 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,953
European (non-Finnish)	0.00424%	23,593
South Asian	0.0033%	30,309
Remaining individualsnot grpmax-eligible	0.00321%	31,145
African / African-American	0.00134%	74,724

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: AMY2B
Protein: p.Arg282Cys
Coding: c.844C>T
MANE Select: NM_001387437
dbSNP: rs368462934
Type: single nucleotide variant
Location: chr1:103574359 (GRCh38)
Gene constraint: LOEUF 1.395 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.70

Full AMY2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMY2B p.Arg282His Uncertain significance ★ ⚠ same residue
AMY2B p.Arg282Leu Uncertain significance ★ ⚠ same residue
AMY2B p.Leu31= Benign/Likely benign ★★ same type
AMY2B p.Ala121Thr Uncertain significance ★ ⚠ same type
AMY2B p.Ala15Thr Uncertain significance ★ ⚠ same type
AMY2B p.Ala339Val Uncertain significance ★ ⚠ same type
AMY2B p.Ala40Val Uncertain significance ★ ⚠ same type
AMY2B p.Ala433Thr 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/amy2b-p-arg282cys (accessed [today's date]).

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