Is BLM p.Arg643His (c.1928G>A) pathogenic?

BLM p.Arg643His (c.1928G>A) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 24 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0627); Rare (popmax 0.557%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Arg643His (c.1928G>A)?

BLM p.Arg643His (c.1928G>A) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Arg643His (c.1928G>A) in the general population?

BLM p.Arg643His (c.1928G>A) is rare (popmax 0.557%, nfe) (gnomAD).

What do computational predictors say about BLM p.Arg643His (c.1928G>A)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

BLM p.Arg643His

c.1928G>A · rs12720097 · VCV127480

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 24 submitters

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.557%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -5
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	2.767	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 0.557% European (non-Finnish) · 6,568/1,179,842 alleles

Filtering AF 0.545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.541%

Overall 0.47% 7,589/1,613,418 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.557%	180
Remaining individualsnot grpmax-eligible	0.4%	250
South Asian	0.391%	256
Middle Eastern	0.38%	263
Ashkenazi Jewishnot grpmax-eligible	0.341%	293
Finnishnot grpmax-eligible	0.25%	400
Admixed American	0.12%	831
African / African-American	0.0747%	1,339
East Asian	0.00891%	11,220

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.Arg643His
Coding: c.1928G>A
MANE Select: NM_000057
dbSNP: rs12720097
Type: single nucleotide variant
Location: chr15:90763011 (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 643: an α-helix

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.Arg643Cys Uncertain significance ★★ ⚠ same residue
BLM p.Arg643Leu Uncertain significance ★★ ⚠ same residue
BLM p.Arg643Ser Uncertain significance ★★ ⚠ same residue
BLM p.Arg643= Likely benign ★★ same residue
BLM p.Arg643fs Pathogenic ★ 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

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-arg643his (accessed [today's date]).

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