Is BLM p.Gln752Lys (c.2254C>A) pathogenic?

BLM p.Gln752Lys (c.2254C>A) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-14). AlphaMissense: ambiguous (0.3936); Very rare (popmax 0.00134%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Gln752Lys (c.2254C>A)?

BLM p.Gln752Lys (c.2254C>A) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Gln752Lys (c.2254C>A) in the general population?

BLM p.Gln752Lys (c.2254C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about BLM p.Gln752Lys (c.2254C>A)?

AlphaMissense predicts ambiguous (score 0.3936) — an in-silico prediction, not a clinical call.

BLM p.Gln752Lys

c.2254C>A · rs1424485988 · VCV1060697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3936	ambiguous
REVEL	0.232	benign-leaning
SaProt	LLR -7.44	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	23.5	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 0.00134% African / African-American · 1/74,762 alleles

Overall 6.23e-05% 1/1,605,280 alleles · very rare exomes 1/1,453,166 · genomes 0/152,114 · 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.Gln752Lys
Coding: c.2254C>A
MANE Select: NM_000057
dbSNP: rs1424485988
Type: single nucleotide variant
Location: chr15:90766970 (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 752: 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.Gln752= Likely benign ★★ same residue
BLM p.Gln752Ter Pathogenic ★ same residue
BLM p.Gln752fs 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
BLM c.1220+2T>G Likely pathogenic ★★ same condition
BLM c.1882+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-gln752lys (accessed [today's date]).

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