Is BLM p.Val4Ala (c.11T>C) pathogenic?

BLM p.Val4Ala (c.11T>C) is classified Conflicting classifications of pathogenicity in BLM (ClinVar, Conflicting submitters, 22 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.46); Rare (popmax 0.2%, nfe); Associated with Hereditary cancer.

What condition is associated with BLM p.Val4Ala (c.11T>C)?

BLM p.Val4Ala (c.11T>C) is associated with Hereditary cancer, Bloom syndrome, hereditary neoplastic syndrome (ClinVar).

How common is BLM p.Val4Ala (c.11T>C) in the general population?

BLM p.Val4Ala (c.11T>C) is rare (popmax 0.2%, nfe) (gnomAD).

What do computational predictors say about BLM p.Val4Ala (c.11T>C)?

AlphaMissense predicts ambiguous (score 0.46) — an in-silico prediction, not a clinical call.

BLM p.Val4Ala

c.11T>C · rs144706057 · VCV127473

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 22 submitters

AlphaMissense

ambiguous

0.46 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.2%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Hereditary cancer

Computational evidence

Protein change
AlphaMissense	0.46	ambiguous
REVEL	0.122	moderately benign-leaning
SaProt	LLR -6.31	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	23.2	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 0.2% European (non-Finnish) · 2,359/1,176,970 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.191%

Overall 0.155% 2,495/1,609,200 alleles · rare exomes 2,339/1,456,902 · genomes 156/152,298 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.2%	499
Remaining individualsnot grpmax-eligible	0.0915%	1,093
Middle Eastern	0.066%	1,514
Admixed American	0.0401%	2,492
Finnishnot grpmax-eligible	0.0394%	2,540
African / African-American	0.0227%	4,411
Ashkenazi Jewishnot grpmax-eligible	0.0068%	14,699
South Asian	0.00663%	15,073
East Asian	0.00223%	44,848

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.Val4Ala
Coding: c.11T>C
MANE Select: NM_000057
dbSNP: rs144706057
Type: single nucleotide variant
Location: chr15:90747403 (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 4: the 'disordered' region

Full BLM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Hereditary cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bloom syndrome hereditary neoplastic syndrome

Similar variants

BLM p.Val4Asp Uncertain significance ★★ ⚠ same residue
BLM p.Val4Phe Uncertain significance ★★ ⚠ same residue
BLM p.Val4Ile Uncertain significance ★ ⚠ same residue
BLM p.Val4Leu Uncertain significance ★ ⚠ same residue
BLM p.Val4= Uncertain significance same residue
BLM p.Val4fs Likely pathogenic ★ same residue
BLM c.1087+1G>A Likely pathogenic ★★ same condition
BLM c.1088-1G>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-val4ala (accessed [today's date]).

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