Is AMY2A p.Arg413Cys (c.1237C>T) pathogenic?

AMY2A p.Arg413Cys (c.1237C>T) is classified Uncertain significance in AMY2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.6429); Ultra-rare (popmax 0.0125%, amr).

How common is AMY2A p.Arg413Cys (c.1237C>T) in the general population?

AMY2A p.Arg413Cys (c.1237C>T) is ultra-rare (popmax 0.0125%, amr) (gnomAD).

What do computational predictors say about AMY2A p.Arg413Cys (c.1237C>T)?

AlphaMissense predicts likely pathogenic (score 0.6429) — an in-silico prediction, not a clinical call.

AMY2A p.Arg413Cys

c.1237C>T · VCV4093466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6429 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6429	likely pathogenic
REVEL	0.499	indeterminate
SaProt	LLR -15.14	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP 0.59, phastCons 0.5
Regional constraint	o/e 0.05	constrained · MANE · 6,189 bp · p 5.7e-50 · regional, not allelic
Overall
CADD	26.2	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 0.0125% Admixed American · 7/56,074 alleles

Filtering AF 0.00867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0081%

Overall 0.0086% 135/1,569,604 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0125%	8,011
European (non-Finnish)	0.0102%	9,818
Remaining individualsnot grpmax-eligible	0.00653%	15,310
Ashkenazi Jewishnot grpmax-eligible	0.00347%	28,842
South Asian	0.00338%	29,550
East Asian	0.00227%	43,966
African / African-American	0.00141%	70,842

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: AMY2A
Protein: p.Arg413Cys
Coding: c.1237C>T
MANE Select: NM_000699
Type: single nucleotide variant
Location: chr1:103624112 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 96.68 · 51 PDB
Residue 413: an α-helix

Full AMY2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMY2A p.Arg413His Uncertain significance ★ ⚠ same residue
AMY2A p.Arg413Leu Uncertain significance ★ ⚠ same residue
AMY2A p.Asn120= Likely benign ★★ same type
AMY2A p.Asn370= Benign/Likely benign ★★ same type
AMY2A p.Thr99Asn Benign ★★ same type
AMY2A p.Ala112Asp Uncertain significance ★ ⚠ same type
AMY2A p.Ala121Thr Uncertain significance ★ ⚠ same type
AMY2A p.Ala124Gly 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/amy2a-p-arg413cys (accessed [today's date]).

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