Is PML p.Met348Val (c.1042A>G) pathogenic?

PML p.Met348Val (c.1042A>G) is classified Uncertain significance in PML (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: ambiguous (0.4739); Very rare (popmax 0.00517%, nfe).

How common is PML p.Met348Val (c.1042A>G) in the general population?

PML p.Met348Val (c.1042A>G) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about PML p.Met348Val (c.1042A>G)?

AlphaMissense predicts ambiguous (score 0.4739) — an in-silico prediction, not a clinical call.

PML p.Met348Val

c.1042A>G · VCV4140404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4739 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4739	ambiguous
REVEL	0.218	benign-leaning
SaProt	LLR -6.53	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 50 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	23.4	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 0.00517% European (non-Finnish) · 61/1,179,674 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00403% 65/1,610,930 alleles · very rare exomes 56/1,458,716 · genomes 9/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,339
African / African-American	0.00401%	24,963
Admixed American	0.00167%	59,982

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.Met348Val
Coding: c.1042A>G
MANE Select: NM_033238
Type: single nucleotide variant
Location: chr15:74023267 (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-met348val (accessed [today's date]).

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