Is PML p.Ile533Val (c.1597A>G) pathogenic?

PML p.Ile533Val (c.1597A>G) is classified Likely benign in PML (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0842); Very rare (popmax 0.00133%, afr).

How common is PML p.Ile533Val (c.1597A>G) in the general population?

PML p.Ile533Val (c.1597A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PML p.Ile533Val (c.1597A>G)?

AlphaMissense predicts likely benign (score 0.0842) — an in-silico prediction, not a clinical call.

PML p.Ile533Val

c.1597A>G · VCV4140411

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0842 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0842	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -4.56	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 -3	GERP -3.3
Regional constraint	o/e 0.85	unconstrained · MANE · 50 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	0.002	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 0.00133% African / African-American · 1/74,942 alleles

Overall 0.000124% 2/1,613,888 alleles · very rare exomes 1/1,461,668 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,942
South Asian	0.0011%	91,084

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.Ile533Val
Coding: c.1597A>G
MANE Select: NM_033238
Type: single nucleotide variant
Location: chr15:74033354 (GRCh38)
Gene constraint: LOEUF 0.613 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 71.17 · 20 PDB
Residue 533: the 'interaction with per2' region; 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-ile533val (accessed [today's date]).

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