Is PDE11A p.Ser757fs (c.2268_2272del) pathogenic?

PDE11A p.Ser757fs (c.22682272del) is classified Pathogenic/Likely pathogenic in PDE11A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-04). Ultra-rare (popmax 0.085%, eas); Associated with pigmented nodular adrenocortical disease, primary, 2.

What condition is associated with PDE11A p.Ser757fs (c.2268_2272del)?

PDE11A p.Ser757fs (c.2268_2272del) is associated with pigmented nodular adrenocortical disease, primary, 2 (ClinVar).

How common is PDE11A p.Ser757fs (c.2268_2272del) in the general population?

PDE11A p.Ser757fs (c.2268_2272del) is ultra-rare (popmax 0.085%, eas) (gnomAD).

PDE11A p.Ser757fs

c.2268_2272del · rs769235876 · VCV225431

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.085%, eas)

Conditions

pigmented nodular adrenocortical disease, primary, 2

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 15 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.9, 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 0.085% East Asian · 38/44,716 alleles

Filtering AF 0.0636% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0562%

Overall 0.00264% 42/1,591,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.085%	1,177
Remaining individualsnot grpmax-eligible	0.00647%	15,445

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.Ser757fs
Coding: c.2268_2272del
MANE Select: NM_016953
dbSNP: rs769235876
Type: Deletion
Location: chr2:177697405 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.12
Residue 757: the pdease domain

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

Disease context

pigmented nodular adrenocortical disease, primary, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE11A p.Ala246fs Likely pathogenic ★ same condition
PDE11A p.Lys119fs Likely pathogenic ★ same condition
PDE11A p.Ser424fs Likely pathogenic ★ same condition
PDE11A p.Arg7fs Conflicting classifications of pathogenicity ★ same condition
PDE11A p.Cys554fs Conflicting classifications of pathogenicity ★ same condition
PDE11A p.Gln46fs Conflicting classifications of pathogenicity ★ same condition
PDE11A p.Gln686fs Uncertain significance ★ same condition
PDE11A p.Leu470fs Uncertain significance ★ same condition

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-ser757fs (accessed [today's date]).

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