Is AMY2A p.Pro49Ala (c.145C>G) pathogenic?

AMY2A p.Pro49Ala (c.145C>G) is classified Uncertain significance in AMY2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-14). AlphaMissense: likely benign (0.1648); Ultra-rare (popmax 0.0695%, nfe).

How common is AMY2A p.Pro49Ala (c.145C>G) in the general population?

AMY2A p.Pro49Ala (c.145C>G) is ultra-rare (popmax 0.0695%, nfe) (gnomAD).

What do computational predictors say about AMY2A p.Pro49Ala (c.145C>G)?

AlphaMissense predicts likely benign (score 0.1648) — an in-silico prediction, not a clinical call.

AMY2A p.Pro49Ala

c.145C>G · rs147709536 · VCV2342111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0695%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1648	likely benign
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -9.33	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 1.7, phastCons 0.9
Regional constraint	o/e 0.94	unconstrained · MANE · 1,667 bp · p 0.42 · regional, not allelic
Overall
CADD	24.7	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 0.0695% European (non-Finnish) · 814/1,170,852 alleles

Filtering AF 0.0655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.064%

Overall 0.055% 881/1,600,576 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0695%	1,438
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,479
Finnishnot grpmax-eligible	0.0397%	2,520
Remaining individualsnot grpmax-eligible	0.0291%	3,437
African / African-American	0.00536%	18,643

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.Pro49Ala
Coding: c.145C>G
MANE Select: NM_000699
dbSNP: rs147709536
Type: single nucleotide variant
Location: chr1:103617585 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 96.68 · 51 PDB
Residue 49: a disulfide bond; a turn

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-pro49ala (accessed [today's date]).

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