Is BLM p.Ser186Ter (c.557C>A) pathogenic?

BLM p.Ser186Ter (c.557C>A) is classified Pathogenic in BLM (ClinVar, Single submitter, 2 submitters; last evaluated 2023-04-28). Ultra-rare (popmax 0.0225%, amr); Associated with Bloom syndrome.

What condition is associated with BLM p.Ser186Ter (c.557C>A)?

BLM p.Ser186Ter (c.557C>A) is associated with Bloom syndrome (ClinVar).

How common is BLM p.Ser186Ter (c.557C>A) in the general population?

BLM p.Ser186Ter (c.557C>A) is ultra-rare (popmax 0.0225%, amr) (gnomAD).

How is Bloom syndrome inherited?

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

BLM p.Ser186Ter

c.557C>A · rs1342383599 · VCV2955983

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0225%, amr)

Conditions

Bloom 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 3 of 22
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.43	GERP -0.21
Overall
CADD	34.0	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 0.0225% Admixed American · 12/53,244 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00153% 22/1,433,362 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0225%	4,437
Ashkenazi Jewishnot grpmax-eligible	0.00708%	14,118
Remaining individualsnot grpmax-eligible	0.00491%	20,361
African / African-American	0.00275%	36,413
European (non-Finnish)	0.000257%	389,622

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.Ser186Ter
Coding: c.557C>A
MANE Select: NM_000057
dbSNP: rs1342383599
Type: single nucleotide variant
Location: chr15:90749825 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.10 · 16 PDB

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.Ser186Pro Uncertain significance ★★ ⚠ same residue
BLM p.Ser186= Likely benign ★★ same residue
BLM p.Ser186_Lys187delinsTer Pathogenic ★★ 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

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-ser186ter (accessed [today's date]).

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