Is BLM p.Val724Ala (c.2171T>C) pathogenic?

BLM p.Val724Ala (c.2171T>C) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-22). AlphaMissense: likely pathogenic (0.8182); Very rare (popmax 0.00654%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Val724Ala (c.2171T>C)?

BLM p.Val724Ala (c.2171T>C) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Val724Ala (c.2171T>C) in the general population?

BLM p.Val724Ala (c.2171T>C) is very rare (popmax 0.00654%, nfe) (gnomAD).

What do computational predictors say about BLM p.Val724Ala (c.2171T>C)?

AlphaMissense predicts likely pathogenic (score 0.8182) — an in-silico prediction, not a clinical call.

BLM p.Val724Ala

c.2171T>C · rs750687788 · VCV567134

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8182 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00654%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8182	likely pathogenic
REVEL	0.473	indeterminate
SaProt	LLR -11.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	27.3	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 0.00654% European (non-Finnish) · 77/1,176,592 alleles

Filtering AF 0.00531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00491%

Overall 0.0054% 87/1,610,124 alleles · very rare exomes 84/1,457,914 · genomes 3/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,929
European (non-Finnish)grpmax	0.00654%	15,280
Finnishnot grpmax-eligible	0.00156%	63,936

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val724Ala
Coding: c.2171T>C
MANE Select: NM_000057
dbSNP: rs750687788
Type: single nucleotide variant
Location: chr15:90765392 (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 724: the helicase atp-binding domain; an α-helix

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.Val724Ile Uncertain significance ★★ ⚠ same residue
BLM p.Val724= Likely benign ★★ same residue
BLM p.Val724Gly Uncertain significance ★ ⚠ same residue
BLM p.Val724Leu 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

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-val724ala (accessed [today's date]).

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