Is BLM p.Glu399Lys (c.1195G>A) pathogenic?

BLM p.Glu399Lys (c.1195G>A) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0876); Ultra-rare (popmax 0.0999%, sas); Associated with Bloom syndrome.

What condition is associated with BLM p.Glu399Lys (c.1195G>A)?

BLM p.Glu399Lys (c.1195G>A) is associated with Bloom syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Glu399Lys (c.1195G>A) in the general population?

BLM p.Glu399Lys (c.1195G>A) is ultra-rare (popmax 0.0999%, sas) (gnomAD).

How is Bloom syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BLM p.Glu399Lys (c.1195G>A)?

AlphaMissense predicts likely benign (score 0.0876) — an in-silico prediction, not a clinical call.

BLM p.Glu399Lys

c.1195G>A · rs538728271 · VCV485334

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0876 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0999%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bloom syndrome

Computational evidence

Protein change
AlphaMissense	0.0876	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.52 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.75	GERP -2, phastCons 0.097
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	17.21	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0999% South Asian · 91/91,068 alleles

Filtering AF 0.0833% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0771%

Overall 0.00613% 99/1,613,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0999%	1,001
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000508%	196,665

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.Glu399Lys
Coding: c.1195G>A
MANE Select: NM_000057
dbSNP: rs538728271
Type: single nucleotide variant
Location: chr15:90760254 (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 399: an α-helix; 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

Bloom syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Bloom syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

BLM p.Glu399Ter Pathogenic ★★ same residue
BLM p.Glu399Asp Uncertain significance ★ ⚠ same residue
BLM p.Glu399Val Uncertain significance ★ ⚠ same residue
BLM p.Glu399Gln Uncertain significance ★ ⚠ 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
BLM c.1220+2T>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-glu399lys (accessed [today's date]).

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