Is PML p.Arg307Cys (c.919C>T) pathogenic?

PML p.Arg307Cys (c.919C>T) is classified Uncertain significance in PML (ClinVar, Single submitter, 2 submitters; last evaluated 2019-09-25). AlphaMissense: likely benign (0.1714); Rare (popmax 0.164%, nfe).

How common is PML p.Arg307Cys (c.919C>T) in the general population?

PML p.Arg307Cys (c.919C>T) is rare (popmax 0.164%, nfe) (gnomAD).

What do computational predictors say about PML p.Arg307Cys (c.919C>T)?

AlphaMissense predicts likely benign (score 0.1714) — an in-silico prediction, not a clinical call.

PML p.Arg307Cys

c.919C>T · rs140050477 · VCV2689792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1714 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.164%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1714	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.014	GERP -0.28
Regional constraint	o/e 0.85	unconstrained · MANE · 50 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	21.8	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 0.164% European (non-Finnish) · 1,935/1,178,312 alleles

Filtering AF 0.158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.156%

Overall 0.129% 2,067/1,604,648 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
European (non-Finnish)grpmax	0.164%	609
Remaining individualsnot grpmax-eligible	0.0707%	1,414
Finnishnot grpmax-eligible	0.0682%	1,466
Admixed American	0.0434%	2,304
African / African-American	0.0253%	3,947
Middle Eastern	0.0171%	5,848
South Asian	0.0011%	90,968

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg307Cys
Coding: c.919C>T
MANE Select: NM_033238
dbSNP: rs140050477
Type: single nucleotide variant
Location: chr15:74023144 (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-arg307cys (accessed [today's date]).

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