Is BLM p.Ala734Ser (c.2200G>T) pathogenic?

BLM p.Ala734Ser (c.2200G>T) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-12). AlphaMissense: likely benign (0.2591); Very rare (popmax 0.00182%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Ala734Ser (c.2200G>T)?

BLM p.Ala734Ser (c.2200G>T) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Ala734Ser (c.2200G>T) in the general population?

BLM p.Ala734Ser (c.2200G>T) is very rare (popmax 0.00182%, nfe) (gnomAD).

What do computational predictors say about BLM p.Ala734Ser (c.2200G>T)?

AlphaMissense predicts likely benign (score 0.2591) — an in-silico prediction, not a clinical call.

BLM p.Ala734Ser

c.2200G>T · rs1301298294 · VCV820876

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2591 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00182%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2591	likely benign
REVEL	0.677	pathogenic-leaning
SaProt	LLR -8.36	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.75	acceptor gain · deltas
Pangolin	Δ0.55	gain · loss 0.29 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	35.0	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 0.00182% European (non-Finnish) · 21/1,151,446 alleles

Filtering AF 0.00117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000995%

Overall 0.00147% 21/1,428,828 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.Ala734Ser
Coding: c.2200G>T
MANE Select: NM_000057
dbSNP: rs1301298294
Type: single nucleotide variant
Location: chr15:90766916 (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 734: the helicase atp-binding domain; a β-strand

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.Ala734Thr Uncertain significance ★★ ⚠ same residue
BLM p.Ala734= Likely benign ★★ same residue
BLM p.Ala734Val 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
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-ala734ser (accessed [today's date]).

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