Is AMY2A p.Arg176His (c.527G>A) pathogenic?

AMY2A p.Arg176His (c.527G>A) is classified Uncertain significance in AMY2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-08). AlphaMissense: likely benign (0.1385); Ultra-rare (popmax 0.0619%, amr).

How common is AMY2A p.Arg176His (c.527G>A) in the general population?

AMY2A p.Arg176His (c.527G>A) is ultra-rare (popmax 0.0619%, amr) (gnomAD).

What do computational predictors say about AMY2A p.Arg176His (c.527G>A)?

AlphaMissense predicts likely benign (score 0.1385) — an in-silico prediction, not a clinical call.

AMY2A p.Arg176His

c.527G>A · rs200283230 · VCV3117198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1385 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0619%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1385	likely benign
REVEL	0.711	pathogenic-leaning
SaProt	LLR -11.32	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 1.4, phastCons 0.99
Regional constraint	o/e 0.05	constrained · MANE · 6,189 bp · p 5.7e-50 · regional, not allelic
Overall
CADD	26.4	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 0.0619% Admixed American · 37/59,812 alleles

Filtering AF 0.0461% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0406%

Overall 0.013% 210/1,610,398 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.295%	339
Admixed Americangrpmax	0.0619%	1,617
Remaining individualsnot grpmax-eligible	0.0224%	4,456
African / African-American	0.0187%	5,345
South Asian	0.00769%	12,999
European (non-Finnish)	0.00416%	24,030
Finnishnot grpmax-eligible	0.00314%	31,834

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg176His
Coding: c.527G>A
MANE Select: NM_000699
dbSNP: rs200283230
Type: single nucleotide variant
Location: chr1:103619567 (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-arg176his (accessed [today's date]).

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