Is BLM p.Lys1133Arg (c.3398A>G) pathogenic?

BLM p.Lys1133Arg (c.3398A>G) is classified Uncertain significance in BLM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-16). AlphaMissense: likely benign (0.0759); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Lys1133Arg (c.3398A>G)?

BLM p.Lys1133Arg (c.3398A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Lys1133Arg (c.3398A>G) in the general population?

BLM p.Lys1133Arg (c.3398A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BLM p.Lys1133Arg (c.3398A>G)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

BLM p.Lys1133Arg

c.3398A>G · rs2505546824 · VCV3224457

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -7.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	20.3	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.Lys1133Arg
Coding: c.3398A>G
MANE Select: NM_000057
dbSNP: rs2505546824
Type: single nucleotide variant
Location: chr15:90803560 (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 1133: the 'dna holliday junction binding' region; a turn

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.Lys1133Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BLM p.Lys1133Asn Uncertain significance ★ ⚠ same residue
BLM p.Lys1133= Likely benign ★ 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-lys1133arg (accessed [today's date]).

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