Is RORB p.Pro414Leu (c.1241C>T) pathogenic?

RORB p.Pro414Leu (c.1241C>T) is classified Likely pathogenic in RORB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely pathogenic (0.753); Absent from gnomAD v4.1.

How common is RORB p.Pro414Leu (c.1241C>T) in the general population?

RORB p.Pro414Leu (c.1241C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RORB p.Pro414Leu (c.1241C>T)?

AlphaMissense predicts likely pathogenic (score 0.753) — an in-silico prediction, not a clinical call.

RORB p.Pro414Leu

c.1241C>T · rs2118583363 · VCV1396998

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.753 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.753	likely pathogenic ✓ concordant with ClinVar
REVEL	0.803	moderately pathogenic-leaning
SaProt	LLR -13.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	acceptor loss, 16 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 20 kb · p 2.1e-06 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P425L vs ClinVar P414L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RORB
Protein: p.Pro414Leu
Coding: c.1241C>T
MANE Select: NM_006914
dbSNP: rs2118583363
Type: single nucleotide variant
Location: chr9:74685479 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 425 UniProt numbering: 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.Pro414= Likely benign ★ same residue
RORB c.94-1G>A Pathogenic/Likely pathogenic ★★ same type
RORB p.Arg214Ter Pathogenic/Likely pathogenic ★★ same type
RORB p.Arg372Ter Pathogenic ★★ same type
RORB p.Arg66Ter Pathogenic/Likely pathogenic ★★ same type
RORB p.Ala269Thr Uncertain significance ★★ ⚠ same type
RORB p.Ala95Thr Uncertain significance ★★ ⚠ same type
RORB p.Arg214Gln 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/rorb-p-pro414leu (accessed [today's date]).

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