Is BTD p.Pro167Leu (c.500C>T) pathogenic?

BTD p.Pro167Leu (c.500C>T) is classified Likely pathogenic in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-01). AlphaMissense: likely benign (0.3018); Very rare (popmax 0.00329%, sas).

How common is BTD p.Pro167Leu (c.500C>T) in the general population?

BTD p.Pro167Leu (c.500C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about BTD p.Pro167Leu (c.500C>T)?

AlphaMissense predicts likely benign (score 0.3018) — an in-silico prediction, not a clinical call.

BTD p.Pro167Leu

c.500C>T · VCV4281583

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3018	likely benign ⚠ discordant with ClinVar
REVEL	0.668	pathogenic-leaning
SaProt	LLR -9.16	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	27.0	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 P187L vs ClinVar P167L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,074 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000274% 4/1,461,892 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,358
European (non-Finnish)	8.47e-05%	1,180,016

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.Pro167Leu
Coding: c.500C>T
MANE Select: NM_001370658
Type: single nucleotide variant
Location: chr3:15644416 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 167: the cn hydrolase domain

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

Similar variants

BTD p.Pro167Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BTD p.Pro167fs 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-pro167leu (accessed [today's date]).

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