Is BLM p.Ser1228fs (c.3681dup) pathogenic?

BLM p.Ser1228fs (c.3681dup) is classified Pathogenic in BLM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-25). Absent from gnomAD; Associated with Bloom syndrome.

What condition is associated with BLM p.Ser1228fs (c.3681dup)?

BLM p.Ser1228fs (c.3681dup) is associated with Bloom syndrome (ClinVar).

How common is BLM p.Ser1228fs (c.3681dup) in the general population?

BLM p.Ser1228fs (c.3681dup) is absent from gnomAD (gnomAD).

How is Bloom syndrome inherited?

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

BLM p.Ser1228fs

c.3681dup · rs367543020 · VCV1444751

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 19 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 0.43, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BLM
Protein: p.Ser1228fs
Coding: c.3681dup
MANE Select: NM_000057
dbSNP: rs367543020
Type: Duplication
Location: chr15:90804286 (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 1228: the 'necessary for ssdna and dna holliday junction binding' region; an α-helix; the hrdc domain

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

For Bloom syndrome (Orphanet):

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

Similar variants

BLM p.Ser1228Tyr Uncertain significance ★★ ⚠ same residue
BLM p.Ser1228Cys Uncertain significance ★ ⚠ same residue
BLM p.Ser1228Phe 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.Leu393fs 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-ser1228fs (accessed [today's date]).

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