Is BLM p.Ser1280Ter (c.3839C>G) pathogenic?

BLM p.Ser1280Ter (c.3839C>G) is classified Pathogenic/Likely pathogenic in BLM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-21). Very rare (popmax 0.00801%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Ser1280Ter (c.3839C>G)?

BLM p.Ser1280Ter (c.3839C>G) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Ser1280Ter (c.3839C>G) in the general population?

BLM p.Ser1280Ter (c.3839C>G) is very rare (popmax 0.00801%, afr) (gnomAD).

BLM p.Ser1280Ter

c.3839C>G · rs1897349804 · VCV2418215

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 20 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.6, phastCons 0.53
Overall
CADD	42.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,892 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000372% 6/1,614,024 alleles · very rare exomes 3/1,461,892 · genomes 3/152,132 · joint denominator

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.Ser1280Ter
Coding: c.3839C>G
MANE Select: NM_000057
dbSNP: rs1897349804
Type: single nucleotide variant
Location: chr15:90809224 (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 1280: an α-helix; the hrdc domain

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.Ser1280= Likely benign ★★ same residue
BLM c.1087+1G>A Likely pathogenic ★★ same condition
BLM c.1088-1G>A Likely pathogenic ★★ same condition
BLM c.1220+2T>C Likely pathogenic ★★ same condition
BLM c.1220+2T>G Likely pathogenic ★★ same condition
BLM c.1882+2T>C Likely pathogenic ★★ same condition
BLM c.2074+1G>T Likely pathogenic ★★ same condition
BLM c.2075-1G>A 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-ser1280ter (accessed [today's date]).

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