Is PDE4A p.Pro331Ser (c.991C>T) pathogenic?

PDE4A p.Pro331Ser (c.991C>T) is classified Benign/Likely benign in PDE4A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1641); Low-frequency (popmax 3.06%, amr).

How common is PDE4A p.Pro331Ser (c.991C>T) in the general population?

PDE4A p.Pro331Ser (c.991C>T) is low-frequency (popmax 3.06%, amr) (gnomAD).

What do computational predictors say about PDE4A p.Pro331Ser (c.991C>T)?

AlphaMissense predicts likely benign (score 0.1641) — an in-silico prediction, not a clinical call.

PDE4A p.Pro331Ser

c.991C>T · rs150660796 · VCV445369

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1641 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.06%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1641	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -9.65	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 4.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 46 kb · p 3.3e-19 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.06% Admixed American · 1,838/60,012 alleles

Filtering AF 2.95% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.9%

Overall 0.134% 2,157/1,613,950 alleles · low-frequency exomes 1,719/1,461,694 · genomes 438/152,256 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	3.06%	33
Remaining individualsnot grpmax-eligible	0.149%	672
South Asian	0.122%	821
African / African-American	0.108%	926
Middle Eastern	0.0165%	6,054
European (non-Finnish)	0.00271%	36,875
East Asian	0.00223%	44,886

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: PDE4A
Protein: p.Pro331Ser
Coding: c.991C>T
MANE Select: NM_001111307
dbSNP: rs150660796
Type: single nucleotide variant
Location: chr19:10457992 (GRCh38)
Gene constraint: LOEUF 0.434 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.87 · 5 PDB
Residue 331: the 'disordered' region

Full PDE4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE4A p.Ala590= Benign ★★ same type
PDE4A p.Arg20= Benign ★★ same type
PDE4A p.Arg608= Benign ★★ same type
PDE4A p.Glu732Gly Benign ★★ same type
PDE4A p.Ser279= Benign ★★ same type
PDE4A c.620+2T>C Uncertain significance ★ same type
PDE4A p.Ala428Thr Uncertain significance ★ ⚠ same type
PDE4A p.Ala508Asp Uncertain significance ★ ⚠ 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/pde4a-p-pro331ser (accessed [today's date]).

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