Is AMY2B p.Arg45Pro (c.134G>C) pathogenic?

AMY2B p.Arg45Pro (c.134G>C) is classified Uncertain significance in AMY2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely pathogenic (0.981); Very rare (popmax 0.00333%, amr).

How common is AMY2B p.Arg45Pro (c.134G>C) in the general population?

AMY2B p.Arg45Pro (c.134G>C) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about AMY2B p.Arg45Pro (c.134G>C)?

AlphaMissense predicts likely pathogenic (score 0.981) — an in-silico prediction, not a clinical call.

AMY2B p.Arg45Pro

c.134G>C · rs558718174 · VCV2485718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.981	likely pathogenic
REVEL	0.669	pathogenic-leaning
SaProt	LLR -14.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 7,894 bp · p 0.74 · regional, not allelic
Overall
CADD	26.8	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 0.00333% Admixed American · 2/59,990 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,611,808 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,995
African / African-American	0.00134%	74,842
European (non-Finnish)	0.000254%	393,275

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.Arg45Pro
Coding: c.134G>C
MANE Select: NM_001387437
dbSNP: rs558718174
Type: single nucleotide variant
Location: chr1:103571736 (GRCh38)
Gene constraint: LOEUF 1.395 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.70
Residue 45: a disulfide bond

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

Similar variants

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
AMY2B p.Ala490Ser Uncertain significance ★ ⚠ same type
AMY2B p.Ala65Thr 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-arg45pro (accessed [today's date]).

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