Is PML p.Thr28Pro (c.82A>C) pathogenic?

PML p.Thr28Pro (c.82A>C) is classified Benign in PML (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-06). AlphaMissense: likely benign (0.0633); Low-frequency (popmax 2.83%, afr).

How common is PML p.Thr28Pro (c.82A>C) in the general population?

PML p.Thr28Pro (c.82A>C) is low-frequency (popmax 2.83%, afr) (gnomAD).

What do computational predictors say about PML p.Thr28Pro (c.82A>C)?

AlphaMissense predicts likely benign (score 0.0633) — an in-silico prediction, not a clinical call.

PML p.Thr28Pro

c.82A>C · rs28504405 · VCV776928

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0633 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.83%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0633	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -4.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.9	GERP -3.6
Regional constraint	o/e 0.85	unconstrained · MANE · 50 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	0.056	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 2.83% African / African-American · 2,050/72,512 alleles

Filtering AF 2.73% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.68%

Overall 0.153% 2,361/1,546,602 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.83%	35
Admixed American	0.188%	531
Remaining individualsnot grpmax-eligible	0.178%	561
Middle Eastern	0.0676%	1,480
European (non-Finnish)	0.00866%	11,550
South Asian	0.00476%	20,996

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: PML
Protein: p.Thr28Pro
Coding: c.82A>C
MANE Select: NM_033238
dbSNP: rs28504405
Type: single nucleotide variant
Location: chr15:73994894 (GRCh38)
Gene constraint: LOEUF 0.613 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 71.17 · 20 PDB
Residue 28: the 'disordered' region

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

Similar variants

PML c.1710+1245A>G Benign ★★ same type
PML c.1710+1270G>T Benign ★★ same type
PML c.1710+1705A>G Benign ★★ same type
PML c.1710+813G>A Benign ★★ same type
PML p.Ala675= Benign ★★ same type
PML p.Pro761= Benign ★★ same type
PML p.Pro791= Benign/Likely benign ★★ same type
PML c.1710+1152C>T 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/pml-p-thr28pro (accessed [today's date]).

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