Is BLM p.Arg15Cys (c.43C>T) pathogenic?

BLM p.Arg15Cys (c.43C>T) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.2712); Ultra-rare (popmax 0.0381%, nfe); Associated with Bloom syndrome.

What condition is associated with BLM p.Arg15Cys (c.43C>T)?

BLM p.Arg15Cys (c.43C>T) is associated with Bloom syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Arg15Cys (c.43C>T) in the general population?

BLM p.Arg15Cys (c.43C>T) is ultra-rare (popmax 0.0381%, 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.Arg15Cys (c.43C>T)?

AlphaMissense predicts likely benign (score 0.2712) — an in-silico prediction, not a clinical call.

BLM p.Arg15Cys

c.43C>T · rs148545569 · VCV236821

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.2712 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0381%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bloom syndrome

Computational evidence

Protein change
AlphaMissense	0.2712	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -8.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.27	acceptor loss, 46 bp away · masked 0 · deltas
Pangolin	Δ0.26	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	27.6	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 0.0381% European (non-Finnish) · 449/1,178,732 alleles

Filtering AF 0.0351% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.034%

Overall 0.0303% 488/1,611,612 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0381%	2,625
Admixed American	0.0284%	3,521
Remaining individualsnot grpmax-eligible	0.0192%	5,198
African / African-American	0.012%	8,318
East Asian	0.00223%	44,856

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.Arg15Cys
Coding: c.43C>T
MANE Select: NM_000057
dbSNP: rs148545569
Type: single nucleotide variant
Location: chr15:90747435 (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 15: the 'disordered' 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.Arg15His Uncertain significance ★★ ⚠ same residue
BLM p.Arg15= Likely benign ★★ same residue
BLM p.Arg15Ser 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
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-arg15cys (accessed [today's date]).

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