Is PDE6B p.Ser700Phe (c.2099C>T) pathogenic?

PDE6B p.Ser700Phe (c.2099C>T) is classified Uncertain significance in PDE6B (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). AlphaMissense: ambiguous (0.4911); Ultra-rare (popmax 0.075%, amr).

How common is PDE6B p.Ser700Phe (c.2099C>T) in the general population?

PDE6B p.Ser700Phe (c.2099C>T) is ultra-rare (popmax 0.075%, amr) (gnomAD).

What do computational predictors say about PDE6B p.Ser700Phe (c.2099C>T)?

AlphaMissense predicts ambiguous (score 0.4911) — an in-silico prediction, not a clinical call.

PDE6B p.Ser700Phe

c.2099C>T · rs752794968 · VCV941139

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.075%, amr)

Computational evidence

Protein change
AlphaMissense	0.4911	ambiguous
REVEL	0.315	indeterminate
SaProt	LLR -8.69	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -3.8, phastCons 0.97
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	28.4	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 0.075% Admixed American · 45/59,996 alleles

Filtering AF 0.0576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.0028% 45/1,608,212 alleles · ultra-rare

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: PDE6B
Protein: p.Ser700Phe
Coding: c.2099C>T
MANE Select: NM_000283
dbSNP: rs752794968
Type: single nucleotide variant
Location: chr4:664191 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 700: the pdease domain

Full PDE6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDE6B p.Ser700= Likely benign ★★ same residue
PDE6B p.Ser700Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PDE6B p.Ser700_Leu701del Uncertain significance ★ same residue
PDE6B c.1059+2T>G Likely pathogenic ★★ same type
PDE6B c.1060-1G>T Pathogenic/Likely pathogenic ★★ same type
PDE6B c.1107+1G>T Likely pathogenic ★★ same type
PDE6B c.1107+3A>G Pathogenic/Likely pathogenic ★★ same type
PDE6B c.1468-2A>G Pathogenic/Likely pathogenic ★★ 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/pde6b-p-ser700phe (accessed [today's date]).

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