Is BTD p.Pro107Leu (c.320C>T) pathogenic?

BTD p.Pro107Leu (c.320C>T) is classified Conflicting classifications of pathogenicity in BTD (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-24). AlphaMissense: ambiguous (0.4258); Very rare (popmax 0.0039%, nfe); Associated with BTD-related disorder.

What condition is associated with BTD p.Pro107Leu (c.320C>T)?

BTD p.Pro107Leu (c.320C>T) is associated with BTD-related disorder, biotinidase deficiency (ClinVar).

How common is BTD p.Pro107Leu (c.320C>T) in the general population?

BTD p.Pro107Leu (c.320C>T) is very rare (popmax 0.0039%, nfe) (gnomAD).

What do computational predictors say about BTD p.Pro107Leu (c.320C>T)?

AlphaMissense predicts ambiguous (score 0.4258) — an in-silico prediction, not a clinical call.

BTD p.Pro107Leu

c.320C>T · rs575787457 · VCV1473153

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Conditions

BTD-related disorder

Computational evidence

Protein change
AlphaMissense	0.4258	ambiguous
REVEL	0.573	indeterminate
SaProt	LLR -14.68	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	26.6	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 P127L vs ClinVar P107L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0039% European (non-Finnish) · 46/1,180,018 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00291% 47/1,613,966 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0039%	25,653
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Pro107Leu
Coding: c.320C>T
MANE Select: NM_001370658
dbSNP: rs575787457
Type: single nucleotide variant
Location: chr3:15641978 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 107: the cn hydrolase domain

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

Disease context

BTD-related disorder

Also linked: biotinidase deficiency

Similar variants

BTD c.1330G>C Pathogenic ★★ same condition
BTD c.249+1G>T Likely pathogenic ★★ same condition
BTD c.400-2A>G Likely pathogenic ★★ same condition
BTD c.-17+2T>C Pathogenic/Likely pathogenic ★★ same condition
BTD p.Ala142Val Pathogenic/Likely pathogenic ★★ same condition
BTD p.Ala217Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
BTD p.Ala269Val Pathogenic/Likely pathogenic ★★ same condition
BTD p.Ala279Pro Pathogenic/Likely pathogenic ★★ same condition

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-pro107leu (accessed [today's date]).

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