Is BLM p.Ile947Thr (c.2840T>C) pathogenic?

BLM p.Ile947Thr (c.2840T>C) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.8256); Ultra-rare (popmax 0.012%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Ile947Thr (c.2840T>C)?

BLM p.Ile947Thr (c.2840T>C) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Ile947Thr (c.2840T>C) in the general population?

BLM p.Ile947Thr (c.2840T>C) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about BLM p.Ile947Thr (c.2840T>C)?

AlphaMissense predicts likely pathogenic (score 0.8256) — an in-silico prediction, not a clinical call.

BLM p.Ile947Thr

c.2840T>C · rs1024172175 · VCV558521

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.8256 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8256	likely pathogenic
REVEL	0.717	pathogenic-leaning
SaProt	LLR -10.59	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 7.8	GERP 2.6, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,926 alleles

Filtering AF 0.00623% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.00112% 18/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,325
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000678%	147,501

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.Ile947Thr
Coding: c.2840T>C
MANE Select: NM_000057
dbSNP: rs1024172175
Type: single nucleotide variant
Location: chr15:90790665 (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 947: an α-helix; the helicase c-terminal domain

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.Ile947Val Conflicting classifications of pathogenicity ★ ⚠ same residue
BLM p.Ile947fs 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
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-ile947thr (accessed [today's date]).

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