Is AMY2B p.Asp188Glu (c.564T>A) pathogenic?

AMY2B p.Asp188Glu (c.564T>A) is classified Uncertain significance in AMY2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.1951); Very rare (popmax 0.000339%, nfe).

How common is AMY2B p.Asp188Glu (c.564T>A) in the general population?

AMY2B p.Asp188Glu (c.564T>A) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about AMY2B p.Asp188Glu (c.564T>A)?

AlphaMissense predicts likely benign (score 0.1951) — an in-silico prediction, not a clinical call.

AMY2B p.Asp188Glu

c.564T>A · VCV4048272

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1951 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1951	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.89	GERP -2.8, phastCons 0.01
Regional constraint	o/e 1.01	unconstrained · MANE · 7,894 bp · p 0.74 · regional, not allelic
Overall
CADD	11.06	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000339% European (non-Finnish) · 4/1,179,758 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,532 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: AMY2B
Protein: p.Asp188Glu
Coding: c.564T>A
MANE Select: NM_001387437
Type: single nucleotide variant
Location: chr1:103573758 (GRCh38)
Gene constraint: LOEUF 1.395 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.70

Full AMY2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMY2B p.Leu31= Benign/Likely benign ★★ same type
AMY2B p.Ala121Thr Uncertain significance ★ ⚠ same type
AMY2B p.Ala15Thr Uncertain significance ★ ⚠ same type
AMY2B p.Ala339Val Uncertain significance ★ ⚠ same type
AMY2B p.Ala40Val Uncertain significance ★ ⚠ same type
AMY2B p.Ala433Thr Uncertain significance ★ ⚠ same type
AMY2B p.Ala490Ser Uncertain significance ★ ⚠ same type
AMY2B p.Ala65Thr 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/amy2b-p-asp188glu (accessed [today's date]).

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