Is BLM p.Arg591Gln (c.1772G>A) pathogenic?

BLM p.Arg591Gln (c.1772G>A) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.0754); Ultra-rare (popmax 0.0177%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Arg591Gln (c.1772G>A)?

BLM p.Arg591Gln (c.1772G>A) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Arg591Gln (c.1772G>A) in the general population?

BLM p.Arg591Gln (c.1772G>A) is ultra-rare (popmax 0.0177%, mid) (gnomAD).

What do computational predictors say about BLM p.Arg591Gln (c.1772G>A)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

BLM p.Arg591Gln

c.1772G>A · rs28385012 · VCV583411

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.51	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 1.5	GERP -0.083, phastCons 0.002
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	17.31	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 0.0177% Middle Eastern · 1/5,662 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000898%

Overall 0.00111% 17/1,531,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0177%	5,662
East Asian	0.00677%	14,770
Admixed American	0.00441%	22,694
Remaining individualsnot grpmax-eligible	0.0017%	58,934
African / African-American	0.00139%	71,994
European (non-Finnish)	0.000786%	127,182

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.Arg591Gln
Coding: c.1772G>A
MANE Select: NM_000057
dbSNP: rs28385012
Type: single nucleotide variant
Location: chr15:90761145 (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 591: the 'necessary for interaction with spidr' region; a UniProt-annotated variant site (in)

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.Arg591Gly Uncertain significance ★★ ⚠ same residue
BLM p.Arg591Trp Uncertain significance ★★ ⚠ same residue
BLM p.Arg591= Likely benign ★ same residue
BLM p.Arg591_Pro592insArg 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-arg591gln (accessed [today's date]).

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