Is BLM p.Thr494fs (c.1479_1480del) pathogenic?

BLM p.Thr494fs (c.14791480del) is classified Pathogenic/Likely pathogenic in BLM (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-31). Very rare (popmax 0.00195%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Thr494fs (c.1479_1480del)?

BLM p.Thr494fs (c.1479_1480del) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Thr494fs (c.1479_1480del) in the general population?

BLM p.Thr494fs (c.1479_1480del) is very rare (popmax 0.00195%, nfe) (gnomAD).

BLM p.Thr494fs

c.1479_1480del · rs746244182 · VCV371108

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00195%, 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 7 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 0.37, phastCons 1
Overall
CADD	18.58	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 0.00195% European (non-Finnish) · 23/1,180,052 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,614,018 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,307
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Thr494fs
Coding: c.1479_1480del
MANE Select: NM_000057
dbSNP: rs746244182
Type: Deletion
Location: chr15:90760851 (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 494: the 'necessary for interaction with spidr' region

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.Thr494Ala Uncertain significance ★★ ⚠ same residue
BLM p.Thr494= Likely benign ★★ same residue
BLM p.Thr494Asn Uncertain significance ★ ⚠ same residue
BLM p.Thr494Ile Conflicting classifications of pathogenicity ★ ⚠ 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

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-thr494fs (accessed [today's date]).

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