Is BTBD2 p.Ser11Pro (c.31T>C) pathogenic?

BTBD2 p.Ser11Pro (c.31T>C) is classified Uncertain significance in BTBD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-09). AlphaMissense: likely benign (0.0723); Very rare (popmax 0.000241%, nfe).

How common is BTBD2 p.Ser11Pro (c.31T>C) in the general population?

BTBD2 p.Ser11Pro (c.31T>C) is very rare (popmax 0.000241%, nfe) (gnomAD).

What do computational predictors say about BTBD2 p.Ser11Pro (c.31T>C)?

AlphaMissense predicts likely benign (score 0.0723) — an in-silico prediction, not a clinical call.

BTBD2 p.Ser11Pro

c.31T>C · VCV3993456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000241%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0723	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -5.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.76, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 18 kb · p 0.86 · regional, not allelic
Overall
CADD	17.47	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 0.000241% European (non-Finnish) · 2/831,156 alleles

Filtering AF 4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.5e-05%

Overall 0.000233% 2/859,376 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: BTBD2
Protein: p.Ser11Pro
Coding: c.31T>C
MANE Select: NM_017797
Type: single nucleotide variant
Location: chr19:2015673 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.28 (gnomAD)
Structure: AlphaFold pLDDT 84.82 · 1 PDB
Residue 11: the 'disordered' region

Full BTBD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD2 p.Ser11Leu Uncertain significance ★ ⚠ same residue
BTBD2 p.Ala201Ser Uncertain significance ★ ⚠ same type
BTBD2 p.Ala201Val Uncertain significance ★ ⚠ same type
BTBD2 p.Ala33Gly Uncertain significance ★ ⚠ same type
BTBD2 p.Ala37Val Uncertain significance ★ ⚠ same type
BTBD2 p.Ala3Thr Uncertain significance ★ ⚠ same type
BTBD2 p.Ala41Glu Uncertain significance ★ ⚠ same type
BTBD2 p.Ala42Ser 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/btbd2-p-ser11pro (accessed [today's date]).

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