Is BLM p.Leu474= (c.1420C>T) pathogenic?

BLM p.Leu474= (c.1420C>T) is classified Likely benign in BLM (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-26). Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Leu474= (c.1420C>T)?

BLM p.Leu474= (c.1420C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Leu474= (c.1420C>T) in the general population?

BLM p.Leu474= (c.1420C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

BLM p.Leu474=

c.1420C>T · rs1596229827 · VCV819178

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.55	GERP -0.92
Overall
CADD	2.162	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,078 alleles

Overall 6.2e-05% 1/1,613,910 alleles · very rare exomes 1/1,461,732 · genomes 0/152,178 · 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.Leu474=
Coding: c.1420C>T
MANE Select: NM_000057
dbSNP: rs1596229827
Type: single nucleotide variant
Location: chr15:90760793 (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 474: 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

Similar variants

BLM p.Leu474Val Uncertain significance ★ ⚠ same residue
BLM p.Leu474Pro Uncertain significance ★ ⚠ same residue
BLM c.2075-1G>A Likely pathogenic ★★ same condition
BLM c.2193+1G>A Pathogenic/Likely pathogenic ★★ same condition
BLM c.2308-2A>G Pathogenic/Likely pathogenic ★★ same condition
BLM c.2407-2A>G Likely pathogenic ★★ same condition
BLM c.2555+1G>A Likely pathogenic ★★ same condition
BLM c.2556-2A>G 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-leu474 (accessed [today's date]).

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