Is BBOF1 p.Phe226Ser (c.677T>C) pathogenic?

BBOF1 p.Phe226Ser (c.677T>C) is classified Uncertain significance in BBOF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely pathogenic (0.7453); Very rare (popmax 0.00267%, afr).

How common is BBOF1 p.Phe226Ser (c.677T>C) in the general population?

BBOF1 p.Phe226Ser (c.677T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about BBOF1 p.Phe226Ser (c.677T>C)?

AlphaMissense predicts likely pathogenic (score 0.7453) — an in-silico prediction, not a clinical call.

BBOF1 p.Phe226Ser

c.677T>C · rs1391423538 · VCV2301165

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7453 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7453	likely pathogenic · top 10% in BBOF1
REVEL	0.424	indeterminate
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 45 kb · p 0.007 · regional, not allelic
Overall
CADD	26.2	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 0.00267% African / African-American · 2/74,898 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,458,210 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: BBOF1
Protein: p.Phe226Ser
Coding: c.677T>C
MANE Select: NM_025057
dbSNP: rs1391423538
Type: single nucleotide variant
Location: chr14:74047959 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.40

Full BBOF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALDH6A1 c.112-11G>T Benign ★★ same type
ALDH6A1 c.731-12T>C Benign/Likely benign ★★ same type
ALDH6A1 c.*494A>T Benign ★★ same type
ALDH6A1 p.Asp137Ala Uncertain significance ★ ⚠ same type
ALDH6A1 p.Met198Leu Uncertain significance ★ ⚠ same type
ALDH6A1 p.Thr96Ile Uncertain significance ★ ⚠ same type
ALDH6A1 p.Val49Ile Conflicting classifications of pathogenicity ★ ⚠ same type
BBOF1 p.Ala317Thr 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/bbof1-p-phe226ser (accessed [today's date]).

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