Is BLM p.Thr321Met (c.962C>T) pathogenic?

BLM p.Thr321Met (c.962C>T) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0607); Very rare (popmax 0.00769%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Thr321Met (c.962C>T)?

BLM p.Thr321Met (c.962C>T) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Thr321Met (c.962C>T) in the general population?

BLM p.Thr321Met (c.962C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about BLM p.Thr321Met (c.962C>T)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

BLM p.Thr321Met

c.962C>T · rs755724766 · VCV1767609

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -8.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.73 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP -0.034, phastCons 0.009
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	13.69	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 0.00769% South Asian · 7/91,028 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000558% 9/1,613,210 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,004
African / African-American	0.00134%	74,872
European (non-Finnish)	8.48e-05%	1,179,665

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.Thr321Met
Coding: c.962C>T
MANE Select: NM_000057
dbSNP: rs755724766
Type: single nucleotide variant
Location: chr15:90754813 (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 321: the 'necessary for interaction with spidr' 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.Thr321= Likely benign ★★ 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
BLM c.2075-1G>A 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-thr321met (accessed [today's date]).

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