Is PDE11A p.Ala48Pro (c.142G>C) pathogenic?

PDE11A p.Ala48Pro (c.142G>C) is classified Uncertain significance in PDE11A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-17). AlphaMissense: likely benign (0.0651); Ultra-rare (popmax 0.0165%, mid).

How common is PDE11A p.Ala48Pro (c.142G>C) in the general population?

PDE11A p.Ala48Pro (c.142G>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PDE11A p.Ala48Pro (c.142G>C)?

AlphaMissense predicts likely benign (score 0.0651) — an in-silico prediction, not a clinical call.

PDE11A p.Ala48Pro

c.142G>C · rs1259167609 · VCV2326863

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0651 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0651	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -5.92	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 0.43	GERP 0.93, phastCons 0.39
Regional constraint	o/e 0.99	unconstrained · MANE · 443 kb · p 0.73 · regional, not allelic
Overall
CADD	10.07	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,638 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	0.00017%	589,946

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.Ala48Pro
Coding: c.142G>C
MANE Select: NM_016953
dbSNP: rs1259167609
Type: single nucleotide variant
Location: chr2:178072296 (GRCh38)
Gene constraint: LOEUF 1.118 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.12
Residue 48: the 'disordered' region

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-ala48pro (accessed [today's date]).

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