Is PDE11A p.Ala453Pro (c.1357G>C) pathogenic?

PDE11A p.Ala453Pro (c.1357G>C) is classified Uncertain significance in PDE11A (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-05). AlphaMissense: likely benign (0.0875); Rare (popmax 0.239%, afr).

How common is PDE11A p.Ala453Pro (c.1357G>C) in the general population?

PDE11A p.Ala453Pro (c.1357G>C) is rare (popmax 0.239%, afr) (gnomAD).

What do computational predictors say about PDE11A p.Ala453Pro (c.1357G>C)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

PDE11A p.Ala453Pro

c.1357G>C · rs142247133 · VCV2347089

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.239%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -7.47	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 0.59	GERP 1.4, phastCons 0.99
Regional constraint	o/e 0.99	unconstrained · MANE · 443 kb · p 0.73 · regional, not allelic
Overall
CADD	18.2	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 0.239% African / African-American · 179/74,960 alleles

Filtering AF 0.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.199%

Overall 0.0122% 197/1,610,058 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.239%	419
Admixed American	0.0183%	5,456
Remaining individualsnot grpmax-eligible	0.0112%	8,910

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.Ala453Pro
Coding: c.1357G>C
MANE Select: NM_016953
dbSNP: rs142247133
Type: single nucleotide variant
Location: chr2:177875869 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.12
Residue 453: 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-ala453pro (accessed [today's date]).

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