Is BTBD3 p.Pro95Ser (c.283C>T) pathogenic?

BTBD3 p.Pro95Ser (c.283C>T) is classified Uncertain significance in BTBD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely benign (0.093); Ultra-rare (popmax 0.0275%, sas).

How common is BTBD3 p.Pro95Ser (c.283C>T) in the general population?

BTBD3 p.Pro95Ser (c.283C>T) is ultra-rare (popmax 0.0275%, sas) (gnomAD).

What do computational predictors say about BTBD3 p.Pro95Ser (c.283C>T)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

BTBD3 p.Pro95Ser

c.283C>T · VCV4646930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0275%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -4.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 100 bp · p 0.3 · regional, not allelic
Overall
CADD	21.5	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 0.0275% South Asian · 25/90,876 alleles

Filtering AF 0.019% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0163%

Overall 0.00167% 27/1,612,908 alleles · ultra-rare exomes 25/1,460,700 · genomes 2/152,208 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0275%	3,635
Admixed American	0.00167%	59,826
European (non-Finnish)	8.48e-05%	1,179,633

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.Pro95Ser
Coding: c.283C>T
MANE Select: NM_014962
Type: single nucleotide variant
Location: chr20:11918558 (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.Pro95Leu Uncertain significance ★ ⚠ same residue
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

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-pro95ser (accessed [today's date]).

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