Is PML p.Pro603Arg (c.1808C>G) pathogenic?

PML p.Pro603Arg (c.1808C>G) is classified Uncertain significance in PML (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: likely benign (0.0999); Ultra-rare (popmax 0.0174%, afr).

How common is PML p.Pro603Arg (c.1808C>G) in the general population?

PML p.Pro603Arg (c.1808C>G) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

What do computational predictors say about PML p.Pro603Arg (c.1808C>G)?

AlphaMissense predicts likely benign (score 0.0999) — an in-silico prediction, not a clinical call.

PML p.Pro603Arg

c.1808C>G · VCV3421380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0999 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0999	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.03	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 2.6	GERP -0.53, phastCons 0.037
Regional constraint	o/e 0.85	unconstrained · MANE · 50 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	12.28	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 0.0174% African / African-American · 13/74,662 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00815%

Overall 0.007% 113/1,613,220 alleles · ultra-rare exomes 104/1,461,894 · genomes 9/151,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,743
Admixed American	0.00835%	11,980
European (non-Finnish)	0.00771%	12,966
Remaining individualsnot grpmax-eligible	0.0064%	15,618

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.Pro603Arg
Coding: c.1808C>G
MANE Select: NM_033238
Type: single nucleotide variant
Location: chr15:74043086 (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-pro603arg (accessed [today's date]).

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