Is BRIX1 p.Arg96Ser (c.286C>A) pathogenic?

BRIX1 p.Arg96Ser (c.286C>A) is classified Uncertain significance in BRIX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-21). AlphaMissense: likely pathogenic (0.9723); Ultra-rare (popmax 0.0156%, eas).

How common is BRIX1 p.Arg96Ser (c.286C>A) in the general population?

BRIX1 p.Arg96Ser (c.286C>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about BRIX1 p.Arg96Ser (c.286C>A)?

AlphaMissense predicts likely pathogenic (score 0.9723) — an in-silico prediction, not a clinical call.

BRIX1 p.Arg96Ser

c.286C>A · VCV3482485

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9723 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9723	likely pathogenic
REVEL	0.158	moderately benign-leaning
SaProt	LLR -10.17	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.60 · evaluated, not missing
Pangolin	Δ0.21	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,753 bp · p 0.54 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 6/38,568 alleles

Filtering AF 0.00677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.000782% 9/1,151,504 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,428
Admixed American	0.00244%	41,048
Remaining individualsnot grpmax-eligible	0.00222%	45,084
South Asian	0.00154%	64,864

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: BRIX1
Protein: p.Arg96Ser
Coding: c.286C>A
MANE Select: NM_018321
Type: single nucleotide variant
Location: chr5:34919854 (GRCh38)
Gene constraint: LOEUF 0.626 · pLI 0.80 (gnomAD)
Structure: AlphaFold pLDDT 81.68 · 10 PDB
Residue 96: the brix domain; a β-strand

Full BRIX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRIX1 p.Ala120Val Uncertain significance ★ ⚠ same type
BRIX1 p.Ala26Gly Uncertain significance ★ ⚠ same type
BRIX1 p.Ala34Ser Uncertain significance ★ ⚠ same type
BRIX1 p.Ala36Glu Uncertain significance ★ ⚠ same type
BRIX1 p.Ala3Val Uncertain significance ★ ⚠ same type
BRIX1 p.Arg218Trp Uncertain significance ★ ⚠ same type
BRIX1 p.Arg267Leu Uncertain significance ★ ⚠ same type
BRIX1 p.Arg270Ile 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/brix1-p-arg96ser (accessed [today's date]).

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