Is BTC p.Arg146Trp (c.436C>T) pathogenic?

BTC p.Arg146Trp (c.436C>T) is classified Uncertain significance in BTC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-14). AlphaMissense: likely benign (0.0911); Ultra-rare (popmax 0.0187%, afr).

How common is BTC p.Arg146Trp (c.436C>T) in the general population?

BTC p.Arg146Trp (c.436C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about BTC p.Arg146Trp (c.436C>T)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

BTC p.Arg146Trp

c.436C>T · VCV3482845

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP 1.3, phastCons 0.99
Regional constraint	o/e 1.10	unconstrained · MANE · 46 kb · p 0.13 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0187% African / African-American · 14/74,702 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00907%

Overall 0.00162% 26/1,603,618 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,336
Admixed American	0.00167%	59,830
European (non-Finnish)	0.000935%	106,911

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: BTC
Protein: p.Arg146Trp
Coding: c.436C>T
MANE Select: NM_001729
Type: single nucleotide variant
Location: chr4:74748142 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.51 · 4 PDB

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

Similar variants

BTC p.Leu44Phe Benign ★★ same type
BTC p.Ala5Val Uncertain significance ★ ⚠ same type
BTC p.Arg106Lys Uncertain significance ★ ⚠ same type
BTC p.Arg148Cys Uncertain significance ★ ⚠ same type
BTC p.Arg37Ile Uncertain significance ★ ⚠ same type
BTC p.Arg6Gly Uncertain significance ★ ⚠ same type
BTC p.Arg6Trp Uncertain significance ★ ⚠ same type
BTC p.Asn42Ser 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/btc-p-arg146trp (accessed [today's date]).

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