Is BTBD3 p.Pro19Ser (c.55C>T) pathogenic?

BTBD3 p.Pro19Ser (c.55C>T) is classified Uncertain significance in BTBD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.9433); Very rare (popmax 0.000254%, nfe).

How common is BTBD3 p.Pro19Ser (c.55C>T) in the general population?

BTBD3 p.Pro19Ser (c.55C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about BTBD3 p.Pro19Ser (c.55C>T)?

AlphaMissense predicts likely pathogenic (score 0.9433) — an in-silico prediction, not a clinical call.

BTBD3 p.Pro19Ser

c.55C>T · VCV4646934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9433 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9433	likely pathogenic
REVEL	0.534	indeterminate
SaProt	LLR -5.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 191 bp · p 0.012 · regional, not allelic
Overall
CADD	31.0	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 0.000254% European (non-Finnish) · 3/1,179,464 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,612,062 alleles · very rare exomes 3/1,459,798 · genomes 0/152,264 · joint denominator

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: BTBD3
Protein: p.Pro19Ser
Coding: c.55C>T
MANE Select: NM_014962
Type: single nucleotide variant
Location: chr20:11918330 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 83.60

Full BTBD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD3 p.Ala303= Benign ★★ same type
BTBD3 p.Ala176Thr Uncertain significance ★ ⚠ same type
BTBD3 p.Ala189Thr Uncertain significance ★ ⚠ same type
BTBD3 p.Ala200Ser Uncertain significance ★ same type
BTBD3 p.Ala303Val Uncertain significance ★ ⚠ same type
BTBD3 p.Ala73Asp Uncertain significance ★ ⚠ same type
BTBD3 p.Ala96Val Uncertain significance ★ ⚠ same type
BTBD3 p.Arg374Leu 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/btbd3-p-pro19ser (accessed [today's date]).

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