Is BLM p.Val765Ala (c.2294T>C) pathogenic?

BLM p.Val765Ala (c.2294T>C) is classified Uncertain significance in BLM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-06). AlphaMissense: ambiguous (0.4264); No allele count reported in gnomAD v4.1 (AN 1,549,610); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Val765Ala (c.2294T>C)?

BLM p.Val765Ala (c.2294T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Val765Ala (c.2294T>C) in the general population?

BLM p.Val765Ala (c.2294T>C) is no allele count reported in gnomAD v4.1 (AN 1,549,610) (gnomAD).

What do computational predictors say about BLM p.Val765Ala (c.2294T>C)?

AlphaMissense predicts ambiguous (score 0.4264) — an in-silico prediction, not a clinical call.

BLM p.Val765Ala

c.2294T>C · rs2505447574 · VCV2586898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4264 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,549,610)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4264	ambiguous
REVEL	0.714	pathogenic-leaning
SaProt	LLR -11.76	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	25.6	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

No allele count reported in gnomAD v4.1 (AN 1,549,610). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BLM
Protein: p.Val765Ala
Coding: c.2294T>C
MANE Select: NM_000057
dbSNP: rs2505447574
Type: single nucleotide variant
Location: chr15:90767010 (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 765: the helicase atp-binding domain; a β-strand

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

Similar variants

BLM p.Val765Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
BLM c.2075-1G>A Likely pathogenic ★★ same condition
BLM c.2193+1G>A Pathogenic/Likely pathogenic ★★ same condition
BLM c.2308-2A>G Pathogenic/Likely pathogenic ★★ same condition
BLM c.2407-2A>G Likely pathogenic ★★ same condition
BLM c.2555+1G>A Likely pathogenic ★★ same condition
BLM c.2556-2A>G Likely pathogenic ★★ same condition
BLM c.2662+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-val765ala (accessed [today's date]).

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