Is PML p.Arg594Ser (c.1782G>C) pathogenic?

PML p.Arg594Ser (c.1782G>C) is classified Uncertain significance in PML (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: likely benign (0.1929); Very rare (popmax 0.0011%, sas).

How common is PML p.Arg594Ser (c.1782G>C) in the general population?

PML p.Arg594Ser (c.1782G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PML p.Arg594Ser (c.1782G>C)?

AlphaMissense predicts likely benign (score 0.1929) — an in-silico prediction, not a clinical call.

PML p.Arg594Ser

c.1782G>C · VCV3421388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1929	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -5.34	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 0.73	GERP -3.3, phastCons 0.18
Regional constraint	o/e 0.85	unconstrained · MANE · 50 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	7.37	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 0.0011% South Asian · 1/91,002 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,346 alleles · very rare exomes 5/1,461,888 · genomes 1/151,458 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,002
European (non-Finnish)	0.000424%	235,976

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.Arg594Ser
Coding: c.1782G>C
MANE Select: NM_033238
Type: single nucleotide variant
Location: chr15:74043060 (GRCh38)
Gene constraint: LOEUF 0.613 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 71.17 · 20 PDB

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-arg594ser (accessed [today's date]).

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