Is BCO1 p.Thr170Met (c.509C>T) pathogenic?

BCO1 p.Thr170Met (c.509C>T) is classified Uncertain significance in BCO1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-10-04). AlphaMissense: ambiguous (0.5239); Rare (popmax 0.224%, nfe); Associated with hereditary hypercarotenemia and vitamin A deficiency.

What condition is associated with BCO1 p.Thr170Met (c.509C>T)?

BCO1 p.Thr170Met (c.509C>T) is associated with hereditary hypercarotenemia and vitamin A deficiency (ClinVar).

How common is BCO1 p.Thr170Met (c.509C>T) in the general population?

BCO1 p.Thr170Met (c.509C>T) is rare (popmax 0.224%, nfe) (gnomAD).

What do computational predictors say about BCO1 p.Thr170Met (c.509C>T)?

AlphaMissense predicts ambiguous (score 0.5239) — an in-silico prediction, not a clinical call.

BCO1 p.Thr170Met

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.509C>T · rs119478057 · VCV4772

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5239 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.224%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary hypercarotenemia and vitamin A deficiency

Computational evidence

Protein change
AlphaMissense	0.5239	ambiguous
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -12.53	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.27	acceptor loss, 37 bp away · masked 0 · deltas
Pangolin	Δ0.28	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 52 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	27.4	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 0.224% European (non-Finnish) · 2,640/1,179,976 alleles

Filtering AF 0.217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.214%

Overall 0.18% 2,905/1,614,096 alleles · rare exomes 2,724/1,461,812 · genomes 181/152,284 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.224%	447
Amishnot grpmax-eligible	0.22%	455
Finnishnot grpmax-eligible	0.212%	471
Remaining individualsnot grpmax-eligible	0.126%	791
African / African-American	0.04%	2,501
Admixed American	0.0167%	6,001
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
South Asian	0.00329%	30,359
East Asian	0.00223%	44,894

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.Thr170Met
Coding: c.509C>T
MANE Select: NM_017429
dbSNP: rs119478057
Type: single nucleotide variant
Location: chr16:81264677 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03
Residue 170: a UniProt-annotated variant site (in hcvad; decreased beta-carotene 15,15'-monooxygenase activity; 90% decrease compared to wild-type; decreased catalytic efficiency; no effect on affinity for all-trans-beta-carotene)

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.Thr170= Likely benign ★ same residue
BCO1 p.Asn142Ser Uncertain significance ★ ⚠ same condition
BCO1 p.Asp493Val Uncertain significance ★ ⚠ same condition
BCO1 p.Cys273Phe 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

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-thr170met (accessed [today's date]).

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