Is BFSP2 p.Pro62His (c.185C>A) pathogenic?

BFSP2 p.Pro62His (c.185C>A) is classified Uncertain significance in BFSP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-11). AlphaMissense: likely benign (0.1145); Very rare (popmax 0.004%, afr); Associated with cataract 12 multiple types.

What condition is associated with BFSP2 p.Pro62His (c.185C>A)?

BFSP2 p.Pro62His (c.185C>A) is associated with cataract 12 multiple types (ClinVar).

How common is BFSP2 p.Pro62His (c.185C>A) in the general population?

BFSP2 p.Pro62His (c.185C>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about BFSP2 p.Pro62His (c.185C>A)?

AlphaMissense predicts likely benign (score 0.1145) — an in-silico prediction, not a clinical call.

BFSP2 p.Pro62His

c.185C>A · rs375248662 · VCV2860615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1145 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cataract 12 multiple types

Computational evidence

Protein change
AlphaMissense	0.1145	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -8.05	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 4.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 75 kb · p 0.73 · regional, not allelic
Overall
CADD	23.4	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 0.004% African / African-American · 3/74,924 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,870 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,975
South Asian	0.0011%	91,074

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.Pro62His
Coding: c.185C>A
MANE Select: NM_003571
dbSNP: rs375248662
Type: single nucleotide variant
Location: chr3:133400268 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.15
Residue 62: the 'head' region

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.Glu289Asp 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

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-pro62his (accessed [today's date]).

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