Is PDE6B p.Met280Val (c.838A>G) pathogenic?

PDE6B p.Met280Val (c.838A>G) is classified Uncertain significance in PDE6B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-09). AlphaMissense: likely benign (0.1809); Ultra-rare (popmax 0.0395%, sas); Associated with Inborn genetic diseases.

What condition is associated with PDE6B p.Met280Val (c.838A>G)?

PDE6B p.Met280Val (c.838A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PDE6B p.Met280Val (c.838A>G) in the general population?

PDE6B p.Met280Val (c.838A>G) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about PDE6B p.Met280Val (c.838A>G)?

AlphaMissense predicts likely benign (score 0.1809) — an in-silico prediction, not a clinical call.

PDE6B p.Met280Val

c.838A>G · rs368480280 · VCV1501784

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1809	likely benign
REVEL	0.609	indeterminate
SaProt	LLR -5.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 44 kb · p 0.27 · regional, not allelic
Overall
CADD	24.4	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 0.0395% South Asian · 36/91,092 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.0044% 71/1,613,728 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
Middle Eastern	0.0164%	6,084
European (non-Finnish)	0.00271%	36,876
Admixed American	0.00167%	60,008
African / African-American	0.00133%	74,930

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.Met280Val
Coding: c.838A>G
MANE Select: NM_000283
dbSNP: rs368480280
Type: single nucleotide variant
Location: chr4:653978 (GRCh38)
Gene constraint: LOEUF 1.238 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.72
Residue 280: the gaf 2 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PDE6B p.Met280Thr Uncertain significance ★ ⚠ same residue
PDE6B p.Ala19Ser Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala341Thr Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala34Thr Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala589Thr Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala809Val Uncertain significance ★★ ⚠ same condition
PDE6B p.Ala845Glu Uncertain significance ★★ ⚠ same condition
PDE6B p.Arg304Cys Uncertain significance ★★ ⚠ same condition

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-met280val (accessed [today's date]).

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