Is AMY2A p.Phe434Leu (c.1300T>C) pathogenic?

AMY2A p.Phe434Leu (c.1300T>C) is classified Uncertain significance in AMY2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-12). AlphaMissense: likely pathogenic (0.9869); Very rare (popmax 0.00242%, eas).

How common is AMY2A p.Phe434Leu (c.1300T>C) in the general population?

AMY2A p.Phe434Leu (c.1300T>C) is very rare (popmax 0.00242%, eas) (gnomAD).

What do computational predictors say about AMY2A p.Phe434Leu (c.1300T>C)?

AlphaMissense predicts likely pathogenic (score 0.9869) — an in-silico prediction, not a clinical call.

AMY2A p.Phe434Leu

c.1300T>C · VCV4093509

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00242%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9869	likely pathogenic · top 7% in AMY2A
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -12.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.05	constrained · MANE · 6,189 bp · p 5.7e-50 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00242% East Asian · 1/41,330 alleles

Overall 0.000103% 1/975,092 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.Phe434Leu
Coding: c.1300T>C
MANE Select: NM_000699
Type: single nucleotide variant
Location: chr1:103624175 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 96.68 · 51 PDB
Residue 434: a β-strand

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-phe434leu (accessed [today's date]).

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