Is BMS1 p.Leu1075Phe (c.3223C>T) pathogenic?

BMS1 p.Leu1075Phe (c.3223C>T) is classified Uncertain significance in BMS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.5229); Very rare (popmax 8.49e-05%, nfe).

How common is BMS1 p.Leu1075Phe (c.3223C>T) in the general population?

BMS1 p.Leu1075Phe (c.3223C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about BMS1 p.Leu1075Phe (c.3223C>T)?

AlphaMissense predicts ambiguous (score 0.5229) — an in-silico prediction, not a clinical call.

BMS1 p.Leu1075Phe

c.3223C>T · VCV4214587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5229	ambiguous
REVEL	0.193	benign-leaning
SaProt	LLR -12.73	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 14 kb · p 1.9e-09 · regional, not allelic
Overall
CADD	21.5	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 8.49e-05% European (non-Finnish) · 1/1,178,286 alleles

Overall 6.87e-05% 1/1,454,592 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: BMS1
Protein: p.Leu1075Phe
Coding: c.3223C>T
MANE Select: NM_014753
Type: single nucleotide variant
Location: chr10:42823208 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.50 (gnomAD)
Structure: AlphaFold pLDDT 72.04 · 3 PDB

Full BMS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BMS1 p.Ala214Val Benign/Likely benign ★★ same type
BMS1 p.Ala500= Benign/Likely benign ★★ same type
BMS1 p.Arg237His Benign ★★ same type
BMS1 p.Arg38Trp Benign/Likely benign ★★ ⚠ same type
BMS1 p.Arg863= Benign ★★ same type
BMS1 p.Asp768Asn Benign ★★ same type
BMS1 p.Glu1278= Likely benign ★★ same type
BMS1 p.Ile942= Benign/Likely benign ★★ 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/bms1-p-leu1075phe (accessed [today's date]).

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