Is BLM p.Leu393fs (c.1176dup) pathogenic?

BLM p.Leu393fs (c.1176dup) is classified Pathogenic in BLM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-16). Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Leu393fs (c.1176dup)?

BLM p.Leu393fs (c.1176dup) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Leu393fs (c.1176dup) in the general population?

BLM p.Leu393fs (c.1176dup) is very rare (popmax 0.00167%, amr) (gnomAD).

BLM p.Leu393fs

c.1176dup · rs1358266880 · VCV1069515

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.3	GERP 0.91, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,012 alleles

Overall 6.84e-05% 1/1,461,794 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: BLM
Protein: p.Leu393fs
Coding: c.1176dup
MANE Select: NM_000057
dbSNP: rs1358266880
Type: Duplication
Location: chr15:90760232 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.10 · 16 PDB
Residue 393: the 'necessary for interaction with spidr' region; the 'necessary for dimerization and homooligomerization' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bloom syndrome

Similar variants

BLM p.Leu393Phe Uncertain significance ★★ ⚠ same residue
BLM p.Leu393Pro Uncertain significance ★ ⚠ same residue
BLM p.Ala481fs Pathogenic ★★ same condition
BLM p.Asp467fs Pathogenic/Likely pathogenic ★★ same condition
BLM p.Leu107fs Pathogenic/Likely pathogenic ★★ same condition
BLM p.Leu342fs Pathogenic/Likely pathogenic ★★ same condition
BLM p.Leu394Ter Pathogenic/Likely pathogenic ★★ same condition
BLM p.Lys657fs Pathogenic ★★ 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/blm-p-leu393fs (accessed [today's date]).

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