Is BTD p.Pro122Thr (c.364C>A) pathogenic?

BTD p.Pro122Thr (c.364C>A) is classified Conflicting classifications of pathogenicity in BTD (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-09-09). AlphaMissense: likely pathogenic (0.6935); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with BTD p.Pro122Thr (c.364C>A)?

BTD p.Pro122Thr (c.364C>A) is associated with Inborn genetic diseases, biotinidase deficiency (ClinVar).

How common is BTD p.Pro122Thr (c.364C>A) in the general population?

BTD p.Pro122Thr (c.364C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about BTD p.Pro122Thr (c.364C>A)?

AlphaMissense predicts likely pathogenic (score 0.6935) — an in-silico prediction, not a clinical call.

BTD p.Pro122Thr

c.364C>A · rs397514357 · VCV25004

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.6935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6935	likely pathogenic
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -16.45	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	26.8	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 P142T vs ClinVar P122T) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,044 alleles

Overall 0.000137% 2/1,461,878 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,502
African / African-Americangrpmax	0.00133%	75,044

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro122Thr
Coding: c.364C>A
MANE Select: NM_001370658
dbSNP: rs397514357
Type: single nucleotide variant
Location: chr3:15642022 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77
Residue 122: the cn hydrolase domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: biotinidase deficiency

Similar variants

BTD p.Pro122Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
BTD p.Pro122= Likely benign ★ same residue
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

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-pro122thr (accessed [today's date]).

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