Is BLM p.Arg1334fs (c.4000_4004del) pathogenic?

BLM p.Arg1334fs (c.40004004del) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-13). Very rare (popmax 0.0011%, sas); Associated with Bloom syndrome.

What condition is associated with BLM p.Arg1334fs (c.4000_4004del)?

BLM p.Arg1334fs (c.4000_4004del) is associated with Bloom syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Arg1334fs (c.4000_4004del) in the general population?

BLM p.Arg1334fs (c.4000_4004del) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Bloom syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

BLM p.Arg1334fs

c.4000_4004del · rs1057516261 · VCV370136

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Bloom 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 21 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3.7	GERP -4.7

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,070 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000342% 5/1,461,886 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
South Asiangrpmax	0.0011%	91,070
European (non-Finnish)	0.000254%	393,312

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1334fs
Coding: c.4000_4004del
MANE Select: NM_000057
dbSNP: rs1057516261
Type: Deletion
Location: chr15:90811327 (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 1334: the 'disordered' region

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

Disease context

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

Also linked: hereditary neoplastic syndrome

For Bloom syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

BLM p.Arg1334= Likely benign ★ same residue
BLM c.2193+1_2193+9del Pathogenic/Likely pathogenic ★★ same condition
BLM c.3013_3019+4del Likely pathogenic ★★ same condition
BLM c.3210+2del Pathogenic/Likely pathogenic ★★ same condition
BLM c.99-8_112del Pathogenic/Likely pathogenic ★★ same condition
BLM p.Arg545fs Pathogenic/Likely pathogenic ★★ same condition
BLM p.Arg836fs Pathogenic ★★ same condition
BLM p.Arg85fs Pathogenic/Likely 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-arg1334fs (accessed [today's date]).

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