Is BLM p.Val765Ile (c.2293G>A) pathogenic?

BLM p.Val765Ile (c.2293G>A) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1551); Rare (popmax 0.223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Val765Ile (c.2293G>A)?

BLM p.Val765Ile (c.2293G>A) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Val765Ile (c.2293G>A) in the general population?

BLM p.Val765Ile (c.2293G>A) is rare (popmax 0.223%, eas) (gnomAD).

What do computational predictors say about BLM p.Val765Ile (c.2293G>A)?

AlphaMissense predicts likely benign (score 0.1551) — an in-silico prediction, not a clinical call.

BLM p.Val765Ile

c.2293G>A · rs191789336 · VCV454099

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1551 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1551	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -9.48	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	25.9	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 0.223% East Asian · 99/44,350 alleles

Filtering AF 0.188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.174%

Overall 0.00974% 151/1,550,928 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.223%	448
South Asian	0.0476%	2,102
Remaining individualsnot grpmax-eligible	0.0149%	6,713
Admixed American	0.00168%	59,458

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.Val765Ile
Coding: c.2293G>A
MANE Select: NM_000057
dbSNP: rs191789336
Type: single nucleotide variant
Location: chr15:90767009 (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

Also linked: hereditary breast ovarian cancer syndrome Bloom syndrome

Similar variants

BLM p.Val765Ala 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
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-val765ile (accessed [today's date]).

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