Is BFSP2 p.His406Asp (c.1216C>G) pathogenic?

BFSP2 p.His406Asp (c.1216C>G) is classified Uncertain significance in BFSP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: ambiguous (0.3569); Very rare (popmax 0.008%, afr).

How common is BFSP2 p.His406Asp (c.1216C>G) in the general population?

BFSP2 p.His406Asp (c.1216C>G) is very rare (popmax 0.008%, afr) (gnomAD).

What do computational predictors say about BFSP2 p.His406Asp (c.1216C>G)?

AlphaMissense predicts ambiguous (score 0.3569) — an in-silico prediction, not a clinical call.

BFSP2 p.His406Asp

c.1216C>G · VCV3991365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3569 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3569	ambiguous
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -10.38	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 75 kb · p 0.73 · regional, not allelic
Overall
CADD	23.7	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 0.008% African / African-American · 6/75,022 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000558% 9/1,612,392 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,504
Admixed American	0.00333%	29,986
Remaining individualsnot grpmax-eligible	0.0016%	62,340

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.His406Asp
Coding: c.1216C>G
MANE Select: NM_003571
Type: single nucleotide variant
Location: chr3:133472537 (GRCh38)
Gene constraint: LOEUF 1.067 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.15
Residue 406: the if rod domain; the 'tail' region

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

Similar variants

BFSP2 p.Arg4Lys Uncertain significance ★★ ⚠ same type
BFSP2 p.Arg52Gln Uncertain significance ★★ ⚠ same type
BFSP2 p.Arg5Ter Uncertain significance ★★ same type
BFSP2 p.Arg72His Uncertain significance ★★ ⚠ same type
BFSP2 p.Glu141Ala Uncertain significance ★★ ⚠ same type
BFSP2 p.Glu228Gly Uncertain significance ★★ ⚠ same type
BFSP2 p.Glu289Asp Uncertain significance ★★ ⚠ same type
BFSP2 p.Gly79Ser 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/bfsp2-p-his406asp (accessed [today's date]).

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