Is BCO1 p.Cys273Phe (c.818G>T) pathogenic?

BCO1 p.Cys273Phe (c.818G>T) is classified Uncertain significance in BCO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely pathogenic (0.8039); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary hypercarotenemia and vitamin A deficiency.

What condition is associated with BCO1 p.Cys273Phe (c.818G>T)?

BCO1 p.Cys273Phe (c.818G>T) is associated with hereditary hypercarotenemia and vitamin A deficiency (ClinVar).

How common is BCO1 p.Cys273Phe (c.818G>T) in the general population?

BCO1 p.Cys273Phe (c.818G>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about BCO1 p.Cys273Phe (c.818G>T)?

AlphaMissense predicts likely pathogenic (score 0.8039) — an in-silico prediction, not a clinical call.

BCO1 p.Cys273Phe

Q: How is Hereditary hypercarotenemia and vitamin A deficiency inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.818G>T · VCV3778888

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8039 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary hypercarotenemia and vitamin A deficiency

Computational evidence

Protein change
AlphaMissense	0.8039	likely pathogenic
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -11.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 52 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.47e-05% European (non-Finnish) · 1/1,179,976 alleles

Overall 6.21e-05% 1/1,610,432 alleles · very rare exomes 1/1,458,168 · genomes 0/152,264 · joint denominator

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.Cys273Phe
Coding: c.818G>T
MANE Select: NM_017429
Type: single nucleotide variant
Location: chr16:81268106 (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

Disease context

hereditary hypercarotenemia and vitamin A deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary hypercarotenemia and vitamin A deficiency (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

BCO1 p.Thr170Met Uncertain significance ★★ ⚠ same condition
BCO1 p.Asn142Ser Uncertain significance ★ ⚠ same condition
BCO1 p.Asp493Val Uncertain significance ★ ⚠ same condition
BCO1 p.Arg266Trp 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

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-cys273phe (accessed [today's date]).

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