Is BLM p.Lys839Arg (c.2516A>G) pathogenic?

BLM p.Lys839Arg (c.2516A>G) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-20). AlphaMissense: likely benign (0.1089); Very rare (popmax 0.00331%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Lys839Arg (c.2516A>G)?

BLM p.Lys839Arg (c.2516A>G) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Lys839Arg (c.2516A>G) in the general population?

BLM p.Lys839Arg (c.2516A>G) is very rare (popmax 0.00331%, nfe) (gnomAD).

What do computational predictors say about BLM p.Lys839Arg (c.2516A>G)?

AlphaMissense predicts likely benign (score 0.1089) — an in-silico prediction, not a clinical call.

BLM p.Lys839Arg

c.2516A>G · rs756815062 · VCV454107

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1089 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00331%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1089	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	22.6	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

Grpmax group 0.00331% European (non-Finnish) · 39/1,179,990 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00242% 39/1,613,992 alleles · very rare exomes 37/1,461,812 · genomes 2/152,180 · 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.Lys839Arg
Coding: c.2516A>G
MANE Select: NM_000057
dbSNP: rs756815062
Type: single nucleotide variant
Location: chr15:90769547 (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 839: the helicase atp-binding domain; an α-helix

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.Lys839Thr Uncertain significance ★★ ⚠ same residue
BLM p.Lys839= Likely benign ★★ same residue
BLM p.Lys839Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BLM p.Lys839del Uncertain significance ★★ same residue
BLM p.Lys839fs Likely 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

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-lys839arg (accessed [today's date]).

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