Is PDE11A p.Glu421= (c.1263A>G) pathogenic?

PDE11A p.Glu421= (c.1263A>G) is classified Benign in PDE11A (ClinVar, Single submitter, 3 submitters; last evaluated 2024-11-26). Common (popmax 14.8%, nfe) — too common for a highly-penetrant pathogenic allele.

PDE11A p.Glu421=

Q: How common is PDE11A p.Glu421= (c.1263A>G) in the general population?

PDE11A p.Glu421= (c.1263A>G) is common (popmax 14.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1263A>G · rs71423514 · VCV3060620

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 14.8%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.082	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.25	GERP -2, phastCons 0.47
Overall
CADD	8.968	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 14.8% European (non-Finnish) · 174,051/1,176,304 alleles

Filtering AF 14.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.7%

Overall 13.3% 214,107/1,610,076 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	22%	5
European (non-Finnish)grpmax	14.8%	7
Remaining individualsnot grpmax-eligible	11.4%	9
South Asian	10.2%	10
Ashkenazi Jewishnot grpmax-eligible	9.51%	11
Amishnot grpmax-eligible	8.77%	11
Middle Eastern	7.99%	13
Admixed American	5.27%	19
African / African-American	2.57%	39
East Asian	2.47%	40

Finnish 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.Glu421=
Coding: c.1263A>G
MANE Select: NM_016953
dbSNP: rs71423514
Type: single nucleotide variant
Location: chr2:177898097 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.12
Residue 421: the gaf 2 domain

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

Similar variants

PDE11A p.Ser604Ter Pathogenic/Likely pathogenic ★★ same type
PDE11A p.Arg329Ter Uncertain significance ★★ same type
PDE11A p.Arg867Trp Uncertain significance ★★ ⚠ same type
PDE11A p.Gln374Ter Uncertain significance ★★ same type
PDE11A p.Pro165Thr Uncertain significance ★★ ⚠ same type
PDE11A p.Pro893Gln Uncertain significance ★★ ⚠ same type
PDE11A p.Tyr658Cys Uncertain significance ★★ ⚠ same type
PDE11A c.1576+26C>T Benign ★★ 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-glu421 (accessed [today's date]).

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