Is BLM p.Ser744Pro (c.2230T>C) pathogenic?

BLM p.Ser744Pro (c.2230T>C) is classified Uncertain significance in BLM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-13). AlphaMissense: ambiguous (0.4369); Very rare (popmax 8.52e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Ser744Pro (c.2230T>C)?

BLM p.Ser744Pro (c.2230T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Ser744Pro (c.2230T>C) in the general population?

BLM p.Ser744Pro (c.2230T>C) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about BLM p.Ser744Pro (c.2230T>C)?

AlphaMissense predicts ambiguous (score 0.4369) — an in-silico prediction, not a clinical call.

BLM p.Ser744Pro

c.2230T>C · VCV4622612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4369 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4369	ambiguous
REVEL	0.181	moderately benign-leaning
SaProt	LLR -9.19	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 5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	25.5	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 8.52e-05% European (non-Finnish) · 1/1,173,274 alleles

Overall 6.23e-05% 1/1,605,844 alleles · very rare exomes 1/1,453,572 · genomes 0/152,272 · 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.Ser744Pro
Coding: c.2230T>C
MANE Select: NM_000057
Type: single nucleotide variant
Location: chr15:90766946 (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 744: the helicase atp-binding domain

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

Similar variants

BLM p.Ser744Leu Uncertain significance ★ ⚠ same residue
BLM p.Ser744= Likely benign ★ same residue
BLM c.2075-1G>A Likely pathogenic ★★ same condition
BLM c.2193+1G>A Pathogenic/Likely pathogenic ★★ same condition
BLM c.2308-2A>G Pathogenic/Likely pathogenic ★★ same condition
BLM c.2407-2A>G Likely pathogenic ★★ same condition
BLM c.2555+1G>A Likely pathogenic ★★ same condition
BLM c.2556-2A>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-ser744pro (accessed [today's date]).

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