Is PDE7B p.Ser249Phe (c.746C>T) pathogenic?

PDE7B p.Ser249Phe (c.746C>T) is classified Uncertain significance in PDE7B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely pathogenic (0.857); Very rare (popmax 0.000424%, nfe).

How common is PDE7B p.Ser249Phe (c.746C>T) in the general population?

PDE7B p.Ser249Phe (c.746C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about PDE7B p.Ser249Phe (c.746C>T)?

AlphaMissense predicts likely pathogenic (score 0.857) — an in-silico prediction, not a clinical call.

PDE7B p.Ser249Phe

c.746C>T · VCV4133893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.857	likely pathogenic
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -10.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 340 kb · p 0.0016 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000424% European (non-Finnish) · 5/1,178,730 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,612,382 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,410
European (non-Finnish)grpmax	0.000424%	235,746

Remaining individuals 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: PDE7B
Protein: p.Ser249Phe
Coding: c.746C>T
MANE Select: NM_018945
Type: single nucleotide variant
Location: chr6:136173831 (GRCh38)
Gene constraint: LOEUF 0.792 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 79.84
Residue 249: the pdease domain

Full PDE7B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE7B p.Lys295Arg Benign/Likely benign ★★ same type
PDE7B p.Ala212Pro Uncertain significance ★ ⚠ same type
PDE7B p.Ala318Ser Uncertain significance ★ ⚠ same type
PDE7B p.Ala318Thr Uncertain significance ★ ⚠ same type
PDE7B p.Arg124Cys Uncertain significance ★ ⚠ same type
PDE7B p.Arg255Gln Uncertain significance ★ ⚠ same type
PDE7B p.Arg293Thr Uncertain significance ★ ⚠ same type
PDE7B p.Arg347Lys 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/pde7b-p-ser249phe (accessed [today's date]).

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