Is BLM p.Ile841Thr (c.2522T>C) pathogenic?

BLM p.Ile841Thr (c.2522T>C) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-05-02). AlphaMissense: likely pathogenic (0.8364); Very rare (popmax 0.00439%, sas); Associated with Bloom syndrome.

What condition is associated with BLM p.Ile841Thr (c.2522T>C)?

BLM p.Ile841Thr (c.2522T>C) is associated with Bloom syndrome (ClinVar).

How common is BLM p.Ile841Thr (c.2522T>C) in the general population?

BLM p.Ile841Thr (c.2522T>C) is very rare (popmax 0.00439%, sas) (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.Ile841Thr (c.2522T>C)?

AlphaMissense predicts likely pathogenic (score 0.8364) — an in-silico prediction, not a clinical call.

BLM p.Ile841Thr

c.2522T>C · rs767086502 · VCV2680171

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8364 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bloom syndrome

Computational evidence

Protein change
AlphaMissense	0.8364	likely pathogenic
REVEL	0.699	pathogenic-leaning
SaProt	LLR -12.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	26.6	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 0.00439% South Asian · 4/91,084 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000274% 4/1,461,802 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.Ile841Thr
Coding: c.2522T>C
MANE Select: NM_000057
dbSNP: rs767086502
Type: single nucleotide variant
Location: chr15:90769553 (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 841: the helicase atp-binding domain; an α-helix; a UniProt-annotated variant site (in blm)

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

For Bloom syndrome (Orphanet):

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

Similar variants

BLM p.Ile841= Likely benign ★ same residue
BLM p.Ile841Asn Uncertain significance ★ ⚠ same residue
BLM p.Ile841Met Uncertain significance ★ ⚠ same residue
BLM p.Ile841Val 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

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-ile841thr (accessed [today's date]).

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