Is BLM p.Leu751fs (c.2250_2251insAAAT) pathogenic?

BLM p.Leu751fs (c.22502251insAAAT) is classified Pathogenic/Likely pathogenic in BLM (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-12-30). Very rare (popmax 0.00153%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Leu751fs (c.2250_2251insAAAT)?

BLM p.Leu751fs (c.2250_2251insAAAT) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Leu751fs (c.2250_2251insAAAT) in the general population?

BLM p.Leu751fs (c.2250_2251insAAAT) is very rare (popmax 0.00153%, nfe) (gnomAD).

BLM p.Leu751fs

c.2250_2251insAAAT · rs786204471 · VCV188790

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

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 10 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.32	GERP 0.15, phastCons 0.99

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,173,560 alleles

Filtering AF 0.000959% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000791%

Overall 0.00138% 20/1,453,664 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,220
European (non-Finnish)grpmax	0.00153%	65,198
African / African-American	0.00134%	74,812

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.Leu751fs
Coding: c.2250_2251insAAAT
MANE Select: NM_000057
dbSNP: rs786204471
Type: Insertion
Location: chr15:90766966 (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 751: the helicase atp-binding domain; an α-helix

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.Leu751Phe Uncertain significance ★★ ⚠ same residue
BLM p.Leu751= Likely benign ★★ same residue
BLM p.Thr1074fs Pathogenic ★★ same condition
BLM p.Ser43_Asp44insTyr Uncertain significance ★★ same condition
BLM p.Thr528delinsIleAla Uncertain significance ★★ same condition
BLM c.741_742insALU Likely pathogenic ★ same condition
BLM p.Asn515Ter Likely pathogenic ★ same condition
BLM p.Asn66delinsThrLeuPheTer 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-leu751fs (accessed [today's date]).

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