Is BCO1 p.Leu331Phe (c.991C>T) pathogenic?

BCO1 p.Leu331Phe (c.991C>T) is classified Uncertain significance in BCO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: ambiguous (0.5311); Very rare (popmax 0.00659%, sas).

How common is BCO1 p.Leu331Phe (c.991C>T) in the general population?

BCO1 p.Leu331Phe (c.991C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about BCO1 p.Leu331Phe (c.991C>T)?

AlphaMissense predicts ambiguous (score 0.5311) — an in-silico prediction, not a clinical call.

BCO1 p.Leu331Phe

c.991C>T · VCV3991122

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5311 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Computational evidence

Protein change
AlphaMissense	0.5311	ambiguous
REVEL	0.627	indeterminate
SaProt	LLR -7.14	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 52 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	25.0	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 0.00659% South Asian · 6/91,082 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000434% 7/1,614,070 alleles · very rare exomes 6/1,461,894 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,180
African / African-American	0.00133%	74,922

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: BCO1
Protein: p.Leu331Phe
Coding: c.991C>T
MANE Select: NM_017429
Type: single nucleotide variant
Location: chr16:81270306 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03

Full BCO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCO1 p.Arg266Trp Uncertain significance ★★ ⚠ same type
BCO1 p.Thr170Met Uncertain significance ★★ ⚠ same type
BCO1 c.1101+48C>T Benign ★★ same type
BCO1 c.1102-81T>C Benign ★★ same type
BCO1 c.1303-13G>A Benign ★★ same type
BCO1 c.1303-70A>G Benign ★★ same type
BCO1 c.194-219A>G Benign ★★ same type
BCO1 c.194-74A>G Benign ★★ 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/bco1-p-leu331phe (accessed [today's date]).

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