Is BTD p.Val422fs (c.1264dup) pathogenic?

BTD p.Val422fs (c.1264dup) is classified Likely pathogenic in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). Very rare (popmax 0.000169%, nfe).

How common is BTD p.Val422fs (c.1264dup) in the general population?

BTD p.Val422fs (c.1264dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

BTD p.Val422fs

c.1264dup · VCV3572379

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,010 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,872 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.Val422fs
Coding: c.1264dup
MANE Select: NM_001370658
Type: Duplication
Location: chr3:15645175 (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

Similar variants

BTD p.Val422Ile Uncertain significance ★★ ⚠ same residue
BTD p.Cys451fs Pathogenic ★★ same type
BTD p.Gly347fs Pathogenic/Likely pathogenic ★★ same type
BTD p.Ile344fs Pathogenic ★★ same type
BTD p.Leu402fs Pathogenic ★★ same type
BTD p.Leu478fs Pathogenic ★★ same type
BTD p.Asn307fs Likely pathogenic ★ same type
BTD p.Asn369fs 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-val422fs (accessed [today's date]).

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