Is AMY2A p.Arg25Trp (c.73C>T) pathogenic?

AMY2A p.Arg25Trp (c.73C>T) is classified Uncertain significance in AMY2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-06). AlphaMissense: ambiguous (0.3757); Ultra-rare (popmax 0.0455%, afr).

How common is AMY2A p.Arg25Trp (c.73C>T) in the general population?

AMY2A p.Arg25Trp (c.73C>T) is ultra-rare (popmax 0.0455%, afr) (gnomAD).

What do computational predictors say about AMY2A p.Arg25Trp (c.73C>T)?

AlphaMissense predicts ambiguous (score 0.3757) — an in-silico prediction, not a clinical call.

AMY2A p.Arg25Trp

c.73C>T · rs145483775 · VCV2526715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3757 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0455%, afr)

Computational evidence

Protein change
AlphaMissense	0.3757	ambiguous
REVEL	0.461	indeterminate
SaProt	LLR -15.66	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3.4
Regional constraint	o/e 0.94	unconstrained · MANE · 1,667 bp · p 0.42 · regional, not allelic
Overall
CADD	24.9	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 0.0455% African / African-American · 34/74,758 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.0167% 268/1,600,718 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0455%	2,199
Finnishnot grpmax-eligible	0.0302%	3,315
European (non-Finnish)	0.0173%	5,767
Remaining individualsnot grpmax-eligible	0.0113%	8,841
South Asian	0.0044%	22,713
Admixed American	0.00167%	59,718

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.Arg25Trp
Coding: c.73C>T
MANE Select: NM_000699
dbSNP: rs145483775
Type: single nucleotide variant
Location: chr1:103617513 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 96.68 · 51 PDB

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-arg25trp (accessed [today's date]).

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