Is RARB p.Ser88= (c.264A>T) pathogenic?

RARB p.Ser88= (c.264A>T) is classified Conflicting classifications of pathogenicity in RARB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-01). Ultra-rare (popmax 0.0329%, mid); Associated with microphthalmia, syndromic 12.

What condition is associated with RARB p.Ser88= (c.264A>T)?

RARB p.Ser88= (c.264A>T) is associated with microphthalmia, syndromic 12 (ClinVar).

How common is RARB p.Ser88= (c.264A>T) in the general population?

RARB p.Ser88= (c.264A>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

RARB p.Ser88=

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.264A>T · rs201295268 · VCV1102389

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

microphthalmia, syndromic 12

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3
Overall
CADD	4.885	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00514% 83/1,613,742 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.0121%	8,279
European (non-Finnish)	0.00568%	17,612
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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.Ser88=
Coding: c.264A>T
MANE Select: NM_000965
dbSNP: rs201295268
Type: single nucleotide variant
Location: chr3:25461299 (GRCh38)
Gene constraint: LOEUF 0.477 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 80.68 · 9 PDB
Residue 88: a DNA-binding region; a β-strand

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-ser88 (accessed [today's date]).

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