Is BLM p.Arg1407Lys (c.4220G>A) pathogenic?

BLM p.Arg1407Lys (c.4220G>A) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.4127); Ultra-rare (popmax 0.0733%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Arg1407Lys (c.4220G>A)?

BLM p.Arg1407Lys (c.4220G>A) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Arg1407Lys (c.4220G>A) in the general population?

BLM p.Arg1407Lys (c.4220G>A) is ultra-rare (popmax 0.0733%, amr) (gnomAD).

What do computational predictors say about BLM p.Arg1407Lys (c.4220G>A)?

AlphaMissense predicts ambiguous (score 0.4127) — an in-silico prediction, not a clinical call.

BLM p.Arg1407Lys

c.4220G>A · rs557057587 · VCV454151

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4127 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0733%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4127	ambiguous
REVEL	0.24	benign-leaning
SaProt	LLR -5.63	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,066 bp · p 0.12 · regional, not allelic
Overall
CADD	23.7	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 0.0733% Admixed American · 44/60,008 alleles

Filtering AF 0.0561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.00347% 56/1,614,058 alleles · ultra-rare exomes 23/1,461,866 · genomes 33/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0733%	1,364
Remaining individualsnot grpmax-eligible	0.016%	6,251
African / African-American	0.00267%	37,505

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.Arg1407Lys
Coding: c.4220G>A
MANE Select: NM_000057
dbSNP: rs557057587
Type: single nucleotide variant
Location: chr15:90815245 (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 1407: the 'disordered' region

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.Arg1407Thr Uncertain significance ★★ ⚠ same residue
BLM p.Arg1407Ser 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
BLM c.2074+1G>T 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-arg1407lys (accessed [today's date]).

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