Is BLM p.Leu394Phe (c.1182G>T) pathogenic?

BLM p.Leu394Phe (c.1182G>T) is classified Uncertain significance in BLM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-25). AlphaMissense: likely benign (0.221); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Leu394Phe (c.1182G>T)?

BLM p.Leu394Phe (c.1182G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Leu394Phe (c.1182G>T) in the general population?

BLM p.Leu394Phe (c.1182G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BLM p.Leu394Phe (c.1182G>T)?

AlphaMissense predicts likely benign (score 0.221) — an in-silico prediction, not a clinical call.

BLM p.Leu394Phe

c.1182G>T · rs2505422328 · VCV2566844

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.221 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.221	likely benign
REVEL	0.411	indeterminate
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.20	donor loss, 38 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BLM
Protein: p.Leu394Phe
Coding: c.1182G>T
MANE Select: NM_000057
dbSNP: rs2505422328
Type: single nucleotide variant
Location: chr15:90760241 (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 394: the 'necessary for interaction with spidr' region; the 'necessary for dimerization and homooligomerization' 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.Leu394= Likely benign ★★ same residue
BLM p.Leu394fs Pathogenic ★★ same residue
BLM p.Leu394Ter Pathogenic/Likely pathogenic ★★ 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

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-leu394phe (accessed [today's date]).

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