Is PDE6B p.Cys84Arg (c.250T>C) pathogenic?

PDE6B p.Cys84Arg (c.250T>C) is classified Uncertain significance in PDE6B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: ambiguous (0.3828); Very rare (popmax 0.00169%, amr).

How common is PDE6B p.Cys84Arg (c.250T>C) in the general population?

PDE6B p.Cys84Arg (c.250T>C) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about PDE6B p.Cys84Arg (c.250T>C)?

AlphaMissense predicts ambiguous (score 0.3828) — an in-silico prediction, not a clinical call.

PDE6B p.Cys84Arg

c.250T>C · rs1487940556 · VCV1053035

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3828	ambiguous
REVEL	0.189	benign-leaning
SaProt	LLR -11.20	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -1.4, phastCons 0.16
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	16.23	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 0.00169% Admixed American · 1/59,114 alleles

Overall 0.000137% 2/1,455,052 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,114
Finnishnot grpmax-eligible	0.00161%	62,222

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.Cys84Arg
Coding: c.250T>C
MANE Select: NM_000283
dbSNP: rs1487940556
Type: single nucleotide variant
Location: chr4:625876 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 84: the gaf 1 domain

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

Similar variants

PDE6B p.Cys84Tyr 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
PDE6B c.1832+1G>T Pathogenic ★★ same type
PDE6B c.1921-1G>A 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-cys84arg (accessed [today's date]).

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