Is BTBD8 p.Leu367Arg (c.1100T>G) pathogenic?

BTBD8 p.Leu367Arg (c.1100T>G) is classified Uncertain significance in BTBD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-08). AlphaMissense: ambiguous (0.3599); Very rare (popmax 0.000339%, nfe).

How common is BTBD8 p.Leu367Arg (c.1100T>G) in the general population?

BTBD8 p.Leu367Arg (c.1100T>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about BTBD8 p.Leu367Arg (c.1100T>G)?

AlphaMissense predicts ambiguous (score 0.3599) — an in-silico prediction, not a clinical call.

BTBD8 p.Leu367Arg

c.1100T>G · rs2526545891 · VCV2544948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3599 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3599	ambiguous
REVEL	0.498	indeterminate
SaProt	LLR -10.88	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 101 kb · p 0.071 · regional, not allelic
Overall
CADD	23.5	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 0.000339% European (non-Finnish) · 4/1,179,742 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,156 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: BTBD8
Protein: p.Leu367Arg
Coding: c.1100T>G
MANE Select: NM_001376131
dbSNP: rs2526545891
Type: single nucleotide variant
Location: chr1:92147764 (GRCh38)
Gene constraint: LOEUF 0.753 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.10

Full BTBD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD8 p.Ala347Ser Uncertain significance ★ ⚠ same type
BTBD8 p.Ala356Thr Uncertain significance ★ ⚠ same type
BTBD8 p.Ala74Val Uncertain significance ★ ⚠ same type
BTBD8 p.Arg79Gly Uncertain significance ★ ⚠ same type
BTBD8 p.Asn181Ser Uncertain significance ★ ⚠ same type
BTBD8 p.Asp170His Uncertain significance ★ ⚠ same type
BTBD8 p.Asp182Val Uncertain significance ★ ⚠ same type
BTBD8 p.Asp209Asn 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/btbd8-p-leu367arg (accessed [today's date]).

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