Is BLM p.Arg407Ser (c.1221A>C) pathogenic?

BLM p.Arg407Ser (c.1221A>C) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-29). AlphaMissense: likely pathogenic (0.9856); Very rare (popmax 0.00467%, nfe); Associated with Bloom syndrome.

What condition is associated with BLM p.Arg407Ser (c.1221A>C)?

BLM p.Arg407Ser (c.1221A>C) is associated with Bloom syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Arg407Ser (c.1221A>C) in the general population?

BLM p.Arg407Ser (c.1221A>C) is very rare (popmax 0.00467%, nfe) (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.Arg407Ser (c.1221A>C)?

AlphaMissense predicts likely pathogenic (score 0.9856) — an in-silico prediction, not a clinical call.

BLM p.Arg407Ser

c.1221A>C · rs900060314 · VCV647847

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00467%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bloom syndrome

Computational evidence

Protein change
AlphaMissense	0.9856	likely pathogenic · top 6% in BLM
REVEL	0.659	pathogenic-leaning
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.40	acceptor gain · deltas
Pangolin	Δ0.49	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.6	GERP 0.34, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	24.4	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 0.00467% European (non-Finnish) · 55/1,177,568 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0033%

Overall 0.00384% 56/1,457,212 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00467%	21,410
African / African-American	0.00133%	74,940

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.Arg407Ser
Coding: c.1221A>C
MANE Select: NM_000057
dbSNP: rs900060314
Type: single nucleotide variant
Location: chr15:90760594 (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 407: an α-helix; the 'necessary for interaction with spidr' region; the 'necessary for dimerization and homooligomerization' region

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

Also linked: hereditary neoplastic syndrome

For Bloom syndrome (Orphanet):

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

Similar variants

BLM p.Arg407Lys Uncertain significance ★★ ⚠ same residue
BLM p.Arg407= Likely benign ★★ same residue
BLM p.Arg407Ile Uncertain significance ★ ⚠ same residue
BLM p.Arg407Thr Conflicting classifications of pathogenicity ★ ⚠ 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-arg407ser (accessed [today's date]).

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