Is BTD p.Ser299Pro (c.895T>C) pathogenic?

BTD p.Ser299Pro (c.895T>C) is classified Uncertain significance in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-16). AlphaMissense: ambiguous (0.5585); Absent from gnomAD v4.1.

How common is BTD p.Ser299Pro (c.895T>C) in the general population?

BTD p.Ser299Pro (c.895T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BTD p.Ser299Pro (c.895T>C)?

AlphaMissense predicts ambiguous (score 0.5585) — an in-silico prediction, not a clinical call.

BTD p.Ser299Pro

c.895T>C · VCV3907092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5585 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.5585	ambiguous
REVEL	0.585	indeterminate
SaProt	LLR -14.06	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S319P vs ClinVar S299P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BTD
Protein: p.Ser299Pro
Coding: c.895T>C
MANE Select: NM_001370658
Type: single nucleotide variant
Location: chr3:15644811 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 319 UniProt numbering: the cn hydrolase domain

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

Similar variants

BTD p.Ser299Phe Likely pathogenic ★ same residue
BTD p.Ser299= Likely benign ★ same residue
BTD c.1330G>C Pathogenic ★★ same type
BTD c.249+1G>T Likely pathogenic ★★ same type
BTD c.400-2A>G Likely pathogenic ★★ same type
BTD c.-17+2T>C Pathogenic/Likely pathogenic ★★ same type
BTD p.Ala142Val Pathogenic/Likely pathogenic ★★ same type
BTD p.Ala217Thr Pathogenic/Likely pathogenic ★★ ⚠ 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/btd-p-ser299pro (accessed [today's date]).

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