Is RORB p.Lys408fs (c.1223del) pathogenic?

RORB p.Lys408fs (c.1223del) is classified Likely pathogenic in RORB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). Absent from gnomAD v4.1.

How common is RORB p.Lys408fs (c.1223del) in the general population?

RORB p.Lys408fs (c.1223del) is absent from gnomAD v4.1 (gnomAD).

RORB p.Lys408fs

c.1223del · VCV3898705

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,583,622)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (9 of 10, 3 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,583,622). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RORB
Protein: p.Lys408fs
Coding: c.1223del
MANE Select: NM_006914
Type: Deletion
Location: chr9:74671898 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 408: the nr lbd domain; a UniProt-annotated variant site (in eig15; loss of subcellular location in the nucleoplasm)

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

Similar variants

RORB p.Lys408= Conflicting classifications of pathogenicity ★ same residue
RORB p.Glu116fs Pathogenic ★ same type
RORB p.Glu232fs Pathogenic ★ same type
RORB p.Glu357fs Pathogenic ★ same type
RORB p.Glu386fs Likely pathogenic ★ same type
RORB p.His21fs Pathogenic ★ same type
RORB p.Leu149fs Pathogenic ★ same type
RORB p.Leu406fs 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/rorb-p-lys408fs (accessed [today's date]).

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