Is BTBD9 p.Leu157Ser (c.470T>C) pathogenic?

BTBD9 p.Leu157Ser (c.470T>C) is classified Uncertain significance in BTBD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). AlphaMissense: likely pathogenic (0.9987); Ultra-rare (popmax 0.0294%, afr).

How common is BTBD9 p.Leu157Ser (c.470T>C) in the general population?

BTBD9 p.Leu157Ser (c.470T>C) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

What do computational predictors say about BTBD9 p.Leu157Ser (c.470T>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

BTBD9 p.Leu157Ser

c.470T>C · rs373994469 · VCV2223767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 7% in BTBD9
REVEL	0.941	strongly pathogenic-leaning
SaProt	LLR -14.56	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 423 kb · p 2.8e-09 · regional, not allelic
Overall
CADD	25.3	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 0.0294% African / African-American · 22/74,938 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00136% 22/1,614,090 alleles · ultra-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: BTBD9
Protein: p.Leu157Ser
Coding: c.470T>C
MANE Select: NM_001099272
dbSNP: rs373994469
Type: single nucleotide variant
Location: chr6:38594043 (GRCh38)
Gene constraint: LOEUF 0.959 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.71
Residue 157: the back domain

Full BTBD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD9 p.Leu157Ile Uncertain significance ★ ⚠ same residue
BTBD9 p.Ala100Val Uncertain significance ★ ⚠ same type
BTBD9 p.Ala28Thr Uncertain significance ★ ⚠ same type
BTBD9 p.Ala476Thr Uncertain significance ★ ⚠ same type
BTBD9 p.Ala590Val Uncertain significance ★ ⚠ same type
BTBD9 p.Ala76Val Uncertain significance ★ ⚠ same type
BTBD9 p.Arg257Gly Uncertain significance ★ ⚠ same type
BTBD9 p.Arg319His 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/btbd9-p-leu157ser (accessed [today's date]).

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