Is RARB p.Pro74= (c.222C>T) pathogenic?

RARB p.Pro74= (c.222C>T) is classified Likely benign in RARB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-25). Very rare (popmax 0.0011%, nfe); Associated with microphthalmia, syndromic 12.

What condition is associated with RARB p.Pro74= (c.222C>T)?

RARB p.Pro74= (c.222C>T) is associated with microphthalmia, syndromic 12 (ClinVar).

How common is RARB p.Pro74= (c.222C>T) in the general population?

RARB p.Pro74= (c.222C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

RARB p.Pro74=

Q: How is Microphthalmia-motor delay-language delay-brain anomalies-diaphragmatic hernia syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.222C>T · VCV4747794

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

microphthalmia, syndromic 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.69	GERP -4.4, phastCons 0.007
Overall
CADD	6.551	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,984 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,614,100 alleles · very rare exomes 13/1,461,840 · genomes 0/152,260 · joint denominator

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: RARB
Protein: p.Pro74=
Coding: c.222C>T
MANE Select: NM_000965
Type: single nucleotide variant
Location: chr3:25461257 (GRCh38)
Gene constraint: LOEUF 0.477 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 80.68 · 9 PDB
Residue 74: the 'modulating' region; the 'disordered' region

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

Disease context

microphthalmia, syndromic 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Microphthalmia-motor delay-language delay-brain anomalies-diaphragmatic hernia syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal

Similar variants

RARB p.Arg387Cys Pathogenic/Likely pathogenic ★★ same condition
RARB p.Gln404Ter Pathogenic/Likely pathogenic ★★ same condition
RARB p.Gly282Ser Pathogenic/Likely pathogenic ★★ same condition
RARB p.Gly384Asp Likely pathogenic ★★ same condition
RARB p.Leu213Pro Pathogenic/Likely pathogenic ★★ same condition
RARB p.Ser398Ter Pathogenic/Likely pathogenic ★★ same condition
RARB p.Arg137Ter Uncertain significance ★★ same condition
RARB p.Asp281Tyr 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/rarb-p-pro74 (accessed [today's date]).

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