Is RORB p.Ser196Arg (c.588C>A) pathogenic?

RORB p.Ser196Arg (c.588C>A) is classified Uncertain significance in RORB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: ambiguous (0.5217); Ultra-rare (popmax 0.0112%, eas).

How common is RORB p.Ser196Arg (c.588C>A) in the general population?

RORB p.Ser196Arg (c.588C>A) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about RORB p.Ser196Arg (c.588C>A)?

AlphaMissense predicts ambiguous (score 0.5217) — an in-silico prediction, not a clinical call.

RORB p.Ser196Arg

c.588C>A · rs567618724 · VCV2986934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5217 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Computational evidence

Protein change
AlphaMissense	0.5217	ambiguous
REVEL	0.361	indeterminate
SaProt	LLR -8.60	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.83, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 18 kb · p 0.076 · regional, not allelic
Overall
CADD	18.43	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 S207R vs ClinVar S196R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% East Asian · 5/44,822 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000434% 7/1,612,132 alleles · ultra-rare exomes 5/1,459,850 · genomes 2/152,282 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0112%	8,964
Remaining individualsnot grpmax-eligible	0.0016%	62,434
South Asian	0.0011%	90,938

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: RORB
Protein: p.Ser196Arg
Coding: c.588C>A
MANE Select: NM_006914
dbSNP: rs567618724
Type: single nucleotide variant
Location: chr9:74642766 (GRCh38)
Gene constraint: LOEUF 0.257 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.48
Residue 207 UniProt numbering: 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 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
RORB p.Arg279Trp 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-ser196arg (accessed [today's date]).

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