Is AMY2A p.Pro69Thr (c.205C>A) pathogenic?

AMY2A p.Pro69Thr (c.205C>A) is classified Uncertain significance in AMY2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.2913); Very rare (popmax 0.0055%, sas).

How common is AMY2A p.Pro69Thr (c.205C>A) in the general population?

AMY2A p.Pro69Thr (c.205C>A) is very rare (popmax 0.0055%, sas) (gnomAD).

What do computational predictors say about AMY2A p.Pro69Thr (c.205C>A)?

AlphaMissense predicts likely benign (score 0.2913) — an in-silico prediction, not a clinical call.

AMY2A p.Pro69Thr

c.205C>A · VCV4640329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2913 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2913	likely benign
REVEL	0.354	indeterminate
SaProt	LLR -11.15	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	acceptor loss, 8 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.9	GERP 1.7
Regional constraint	o/e 0.94	unconstrained · MANE · 1,667 bp · p 0.42 · regional, not allelic
Overall
CADD	21.4	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 0.0055% South Asian · 5/90,860 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.000562% 9/1,600,318 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0055%	18,172
Remaining individualsnot grpmax-eligible	0.00323%	30,930
African / African-American	0.00134%	74,604
European (non-Finnish)	8.54e-05%	1,170,644

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.Pro69Thr
Coding: c.205C>A
MANE Select: NM_000699
Type: single nucleotide variant
Location: chr1:103617990 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 96.68 · 51 PDB
Residue 69: 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-pro69thr (accessed [today's date]).

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