Is BTD p.Phe423Cys (c.1268T>G) pathogenic?

BTD p.Phe423Cys (c.1268T>G) is classified Uncertain significance in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-08). AlphaMissense: likely pathogenic (0.8547); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BTD p.Phe423Cys (c.1268T>G)?

BTD p.Phe423Cys (c.1268T>G) is associated with Inborn genetic diseases (ClinVar).

How common is BTD p.Phe423Cys (c.1268T>G) in the general population?

BTD p.Phe423Cys (c.1268T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BTD p.Phe423Cys (c.1268T>G)?

AlphaMissense predicts likely pathogenic (score 0.8547) — an in-silico prediction, not a clinical call.

BTD p.Phe423Cys

c.1268T>G · VCV3825969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8547 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8547	likely pathogenic
REVEL	0.953	strongly pathogenic-leaning
SaProt	LLR -12.42	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 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F443C vs ClinVar F423C) — 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.Phe423Cys
Coding: c.1268T>G
MANE Select: NM_001370658
Type: single nucleotide variant
Location: chr3:15645184 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.77

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

Similar variants

BTD p.Phe423Tyr Uncertain significance ★ ⚠ same residue
BTD p.Gly94Val Pathogenic/Likely pathogenic ★★ same condition
BTD p.His465Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
BTD p.Asn152Ser Uncertain significance ★★ ⚠ same condition
BTD p.Asp304Glu Uncertain significance ★★ ⚠ same condition
BTD p.Asp348Ala Uncertain significance ★★ ⚠ same condition
BTD p.Cys351Arg Uncertain significance ★★ ⚠ same condition
BTD p.Gln68His Uncertain significance ★★ ⚠ 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-phe423cys (accessed [today's date]).

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