Is BFSP2 p.Glu289Asp (c.867G>C) pathogenic?

BFSP2 p.Glu289Asp (c.867G>C) is classified Uncertain significance in BFSP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-26). AlphaMissense: likely benign (0.1462); Ultra-rare (popmax 0.0916%, amr); Associated with cataract 12 multiple types.

What condition is associated with BFSP2 p.Glu289Asp (c.867G>C)?

BFSP2 p.Glu289Asp (c.867G>C) is associated with cataract 12 multiple types (ClinVar).

How common is BFSP2 p.Glu289Asp (c.867G>C) in the general population?

BFSP2 p.Glu289Asp (c.867G>C) is ultra-rare (popmax 0.0916%, amr) (gnomAD).

What do computational predictors say about BFSP2 p.Glu289Asp (c.867G>C)?

AlphaMissense predicts likely benign (score 0.1462) — an in-silico prediction, not a clinical call.

BFSP2 p.Glu289Asp

c.867G>C · rs200862865 · VCV856280

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1462 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0916%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cataract 12 multiple types

Computational evidence

Protein change
AlphaMissense	0.1462	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -7.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -2.1, phastCons 0.95
Regional constraint	o/e 0.99	unconstrained · MANE · 75 kb · p 0.73 · regional, not allelic
Overall
CADD	16.94	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0916% Admixed American · 55/60,022 alleles

Filtering AF 0.0722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0653%

Overall 0.00347% 56/1,614,102 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0916%	1,091
European (non-Finnish)	8.47e-05%	1,180,018

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: BFSP2
Protein: p.Glu289Asp
Coding: c.867G>C
MANE Select: NM_003571
dbSNP: rs200862865
Type: single nucleotide variant
Location: chr3:133450440 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.15
Residue 289: the if rod domain

Full BFSP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 12 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BFSP2 p.Arg4Lys Uncertain significance ★★ ⚠ same condition
BFSP2 p.Arg5Ter Uncertain significance ★★ same condition
BFSP2 p.Arg72His Uncertain significance ★★ ⚠ same condition
BFSP2 p.Glu141Ala Uncertain significance ★★ ⚠ same condition
BFSP2 p.Leu153Gln Uncertain significance ★★ ⚠ same condition
BFSP2 c.572+160A>G Benign ★★ same condition
BFSP2 c.730-7T>C Benign/Likely benign ★★ same condition
BFSP2 p.Ala201= Benign ★★ 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/bfsp2-p-glu289asp (accessed [today's date]).

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