Is BTD p.Ser291Thr (c.872G>C) pathogenic?

BTD p.Ser291Thr (c.872G>C) is classified Uncertain significance in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: ambiguous (0.3727); Very rare (popmax 0.00133%, afr).

How common is BTD p.Ser291Thr (c.872G>C) in the general population?

BTD p.Ser291Thr (c.872G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BTD p.Ser291Thr (c.872G>C)?

AlphaMissense predicts ambiguous (score 0.3727) — an in-silico prediction, not a clinical call.

BTD p.Ser291Thr

c.872G>C · VCV3768256

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3727	ambiguous
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -9.87	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	27.4	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 S311T vs ClinVar S291T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,012 alleles

Overall 6.84e-05% 1/1,461,888 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: BTD
Protein: p.Ser291Thr
Coding: c.872G>C
MANE Select: NM_001370658
Type: single nucleotide variant
Location: chr3:15644788 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 291: the cn hydrolase domain

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

Similar variants

BTD p.Ser291Asn Pathogenic/Likely pathogenic ★★ same residue
BTD p.Ser291fs Pathogenic/Likely pathogenic ★★ 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-ser291thr (accessed [today's date]).

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