Is PDE11A p.Met445fs (c.1332del) pathogenic?

PDE11A p.Met445fs (c.1332del) is classified Uncertain significance in PDE11A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-08). Ultra-rare (popmax 0.0107%, nfe).

How common is PDE11A p.Met445fs (c.1332del) in the general population?

PDE11A p.Met445fs (c.1332del) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

PDE11A p.Met445fs

c.1332del · rs757360600 · VCV1213493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.39	GERP -4.5, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% European (non-Finnish) · 126/1,178,468 alleles

Filtering AF 0.00912% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00856%

Overall 0.00837% 135/1,612,270 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,919
European (non-Finnish)grpmax	0.0107%	9,353
African / African-American	0.00267%	37,430

Remaining individuals 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: PDE11A
Protein: p.Met445fs
Coding: c.1332del
MANE Select: NM_016953
dbSNP: rs757360600
Type: Deletion
Location: chr2:177875894 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.12
Residue 445: the gaf 2 domain

Full PDE11A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE11A p.Ser757fs Pathogenic/Likely pathogenic ★★ same type
PDE11A p.Ala156fs Uncertain significance ★★ same type
PDE11A p.Ala246fs Likely pathogenic ★ same type
PDE11A p.Arg154fs Likely pathogenic ★ same type
PDE11A p.Lys119fs Likely pathogenic ★ same type
PDE11A p.Ser424fs Likely pathogenic ★ same type
PDE11A p.Arg17fs Uncertain significance ★ same type
PDE11A p.Arg7fs Conflicting classifications of pathogenicity ★ 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/pde11a-p-met445fs (accessed [today's date]).

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