Is BTD p.Glu416Ala (c.1247A>C) pathogenic?

BTD p.Glu416Ala (c.1247A>C) is classified Uncertain significance in BTD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: ambiguous (0.5555); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with BTD p.Glu416Ala (c.1247A>C)?

BTD p.Glu416Ala (c.1247A>C) is associated with Inborn genetic diseases (ClinVar).

How common is BTD p.Glu416Ala (c.1247A>C) in the general population?

BTD p.Glu416Ala (c.1247A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BTD p.Glu416Ala (c.1247A>C)?

AlphaMissense predicts ambiguous (score 0.5555) — an in-silico prediction, not a clinical call.

BTD p.Glu416Ala

c.1247A>C · VCV3482850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5555 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5555	ambiguous
REVEL	0.882	moderately pathogenic-leaning
SaProt	LLR -11.64	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 10 kb · p 0.35 · regional, not allelic
Overall
CADD	25.6	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 E436A vs ClinVar E416A) — 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.Glu416Ala
Coding: c.1247A>C
MANE Select: NM_001370658
Type: single nucleotide variant
Location: chr3:15645163 (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.Glu416Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
BTD p.Glu416= Likely benign ★ same residue
BTD p.Glu416fs Pathogenic/Likely pathogenic ★★ 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

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-glu416ala (accessed [today's date]).

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