Is BLM p.Asp554Val (c.1661A>T) pathogenic?

BLM p.Asp554Val (c.1661A>T) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-12). AlphaMissense: likely benign (0.1956); Ultra-rare (popmax 0.0168%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Asp554Val (c.1661A>T)?

BLM p.Asp554Val (c.1661A>T) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Asp554Val (c.1661A>T) in the general population?

BLM p.Asp554Val (c.1661A>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about BLM p.Asp554Val (c.1661A>T)?

AlphaMissense predicts likely benign (score 0.1956) — an in-silico prediction, not a clinical call.

BLM p.Asp554Val

c.1661A>T · rs1266070433 · VCV1420427

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1956 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1956	likely benign
REVEL	0.355	indeterminate
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.20	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 16 kb · p 0.23 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0168% Middle Eastern · 1/5,962 alleles

Overall 0.000188% 3/1,597,148 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,962
Remaining individualsnot grpmax-eligible	0.00162%	61,688
African / African-American	0.00136%	73,748

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.Asp554Val
Coding: c.1661A>T
MANE Select: NM_000057
dbSNP: rs1266070433
Type: single nucleotide variant
Location: chr15:90761034 (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 554: 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.Asp554Asn 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-asp554val (accessed [today's date]).

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