Is AMY2A p.Pro136Arg (c.407C>G) pathogenic?

AMY2A p.Pro136Arg (c.407C>G) is classified Uncertain significance in AMY2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-09). AlphaMissense: ambiguous (0.4909); Very rare (popmax 9.95e-05%, nfe).

How common is AMY2A p.Pro136Arg (c.407C>G) in the general population?

AMY2A p.Pro136Arg (c.407C>G) is very rare (popmax 9.95e-05%, nfe) (gnomAD).

What do computational predictors say about AMY2A p.Pro136Arg (c.407C>G)?

AlphaMissense predicts ambiguous (score 0.4909) — an in-silico prediction, not a clinical call.

AMY2A p.Pro136Arg

c.407C>G · VCV3536932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.95e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4909	ambiguous
REVEL	0.465	indeterminate
SaProt	LLR -15.40	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.2, phastCons 0.053
Regional constraint	o/e 0.94	unconstrained · MANE · 1,667 bp · p 0.42 · regional, not allelic
Overall
CADD	22.6	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 9.95e-05% European (non-Finnish) · 1/1,005,492 alleles

Overall 8.15e-05% 1/1,227,744 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: AMY2A
Protein: p.Pro136Arg
Coding: c.407C>G
MANE Select: NM_000699
Type: single nucleotide variant
Location: chr1:103619002 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 96.68 · 51 PDB
Residue 136: an α-helix

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

Similar variants

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
AMY2A p.Ala65Thr Uncertain significance ★ ⚠ same type
AMY2A p.Arg107Cys 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-pro136arg (accessed [today's date]).

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