Is BLM p.Pro868Gln (c.2603C>A) pathogenic?

BLM p.Pro868Gln (c.2603C>A) is classified Uncertain significance in BLM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.2044); Very rare (popmax 6.84e-05%); Associated with Bloom syndrome.

What condition is associated with BLM p.Pro868Gln (c.2603C>A)?

BLM p.Pro868Gln (c.2603C>A) is associated with Bloom syndrome (ClinVar).

How common is BLM p.Pro868Gln (c.2603C>A) in the general population?

BLM p.Pro868Gln (c.2603C>A) is very rare (popmax 6.84e-05%) (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.Pro868Gln (c.2603C>A)?

AlphaMissense predicts likely benign (score 0.2044) — an in-silico prediction, not a clinical call.

BLM p.Pro868Gln

c.2603C>A · rs2227935 · VCV855803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2044 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bloom syndrome

Computational evidence

Protein change
AlphaMissense	0.2044	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.47	acceptor gain · deltas
Pangolin	Δ0.53	gain · loss 0.34 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 0.93, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	24.4	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 6.84e-05%

Overall 6.84e-05% 1/1,461,382 alleles · very rare

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.Pro868Gln
Coding: c.2603C>A
MANE Select: NM_000057
dbSNP: rs2227935
Type: single nucleotide variant
Location: chr15:90782869 (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 868: a β-strand; a UniProt-annotated variant site (in)

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

For Bloom syndrome (Orphanet):

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

Similar variants

BLM p.Pro868Arg Uncertain significance ★★ ⚠ same residue
BLM p.Pro868= Likely benign ★★ same residue
BLM p.Pro868Leu Benign/Likely benign ★★ ⚠ same residue
BLM p.Pro868_Lys869delinsLeuGlu Benign ★ same residue
BLM p.Pro868fs Benign ★ 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-pro868gln (accessed [today's date]).

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