Is BFSP2 p.Leu234Pro (c.701T>C) pathogenic?

BFSP2 p.Leu234Pro (c.701T>C) is classified Uncertain significance in BFSP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.8526); Very rare (popmax 0.00381%, nfe); Associated with cataract 12 multiple types.

What condition is associated with BFSP2 p.Leu234Pro (c.701T>C)?

BFSP2 p.Leu234Pro (c.701T>C) is associated with cataract 12 multiple types (ClinVar).

How common is BFSP2 p.Leu234Pro (c.701T>C) in the general population?

BFSP2 p.Leu234Pro (c.701T>C) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about BFSP2 p.Leu234Pro (c.701T>C)?

AlphaMissense predicts likely pathogenic (score 0.8526) — an in-silico prediction, not a clinical call.

BFSP2 p.Leu234Pro

c.701T>C · rs886058011 · VCV343410

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8526 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 12 multiple types

Computational evidence

Protein change
AlphaMissense	0.8526	likely pathogenic
REVEL	0.798	moderately pathogenic-leaning
SaProt	LLR -10.26	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4	GERP 0.77, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 75 kb · p 0.73 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00381% European (non-Finnish) · 45/1,179,982 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00308% 45/1,461,684 alleles · very rare

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.Leu234Pro
Coding: c.701T>C
dbSNP: rs886058011
Type: single nucleotide variant
Location: chr3:133448617 (GRCh38)

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

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-leu234pro (accessed [today's date]).

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