Is BTBD7 p.Leu541Phe (c.1623G>C) pathogenic?

BTBD7 p.Leu541Phe (c.1623G>C) is classified Uncertain significance in BTBD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely benign (0.2979); Very rare (popmax 8.6e-05%, nfe).

How common is BTBD7 p.Leu541Phe (c.1623G>C) in the general population?

BTBD7 p.Leu541Phe (c.1623G>C) is very rare (popmax 8.6e-05%, nfe) (gnomAD).

What do computational predictors say about BTBD7 p.Leu541Phe (c.1623G>C)?

AlphaMissense predicts likely benign (score 0.2979) — an in-silico prediction, not a clinical call.

BTBD7 p.Leu541Phe

c.1623G>C · VCV3482818

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.6e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2979	likely benign
REVEL	0.429	indeterminate
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.7	GERP -0.94, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 15 kb · p 0.075 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.6e-05% European (non-Finnish) · 1/1,163,044 alleles

Overall 6.98e-05% 1/1,433,536 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: BTBD7
Protein: p.Leu541Phe
Coding: c.1623G>C
MANE Select: NM_001002860
Type: single nucleotide variant
Location: chr14:93253776 (GRCh38)
Gene constraint: LOEUF 0.542 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 61.50

Full BTBD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTBD7 p.Ala110Thr Uncertain significance ★ ⚠ same type
BTBD7 p.Ala158Thr Uncertain significance ★ ⚠ same type
BTBD7 p.Ala359Ser Uncertain significance ★ ⚠ same type
BTBD7 p.Ala3Val Uncertain significance ★ ⚠ same type
BTBD7 p.Ala491Asp Uncertain significance ★ ⚠ same type
BTBD7 p.Ala567Ser Uncertain significance ★ ⚠ same type
BTBD7 p.Ala567Val Uncertain significance ★ ⚠ same type
BTBD7 p.Ala675Ser Uncertain significance ★ ⚠ 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/btbd7-p-leu541phe (accessed [today's date]).

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