Is BFSP2 p.Ala407Asp (c.1220C>A) pathogenic?

BFSP2 p.Ala407Asp (c.1220C>A) is classified Benign in BFSP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1392); Common (popmax 7.14%, mid) — too common for a highly-penetrant pathogenic allele; Associated with cataract 12 multiple types.

What condition is associated with BFSP2 p.Ala407Asp (c.1220C>A)?

BFSP2 p.Ala407Asp (c.1220C>A) is associated with cataract 12 multiple types (ClinVar).

What do computational predictors say about BFSP2 p.Ala407Asp (c.1220C>A)?

AlphaMissense predicts likely benign (score 0.1392) — an in-silico prediction, not a clinical call.

BFSP2 p.Ala407Asp

Q: How common is BFSP2 p.Ala407Asp (c.1220C>A) in the general population?

BFSP2 p.Ala407Asp (c.1220C>A) is common (popmax 7.14%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1220C>A · rs79087781 · VCV259089

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1392 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.14%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cataract 12 multiple types

Computational evidence

Protein change
AlphaMissense	0.1392	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -7.14	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 1.4	GERP -3.8, phastCons 0.91
Regional constraint	o/e 0.99	unconstrained · MANE · 75 kb · p 0.73 · regional, not allelic
Overall
CADD	20.7	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 7.14% Middle Eastern · 336/4,708 alleles

Filtering AF 6.51% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.26%

Overall 4.35% 70,192/1,612,172 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	7.14%	14
Ashkenazi Jewishnot grpmax-eligible	6.86%	15
South Asian	6.36%	16
Remaining individualsnot grpmax-eligible	4.66%	21
Finnishnot grpmax-eligible	4.52%	22
European (non-Finnish)	4.32%	23
African / African-American	3.59%	28
Admixed American	2.95%	34
East Asian	1.88%	53
Amishnot grpmax-eligible	1.43%	70

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.Ala407Asp
Coding: c.1220C>A
MANE Select: NM_003571
dbSNP: rs79087781
Type: single nucleotide variant
Location: chr3:133472541 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.15
Residue 407: the if rod domain; the 'tail' 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-ala407asp (accessed [today's date]).

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