Is BLM p.Gly1046Ser (c.3136G>A) pathogenic?

BLM p.Gly1046Ser (c.3136G>A) is classified Uncertain significance in BLM (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-24). AlphaMissense: ambiguous (0.36); Ultra-rare (popmax 0.0107%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with BLM p.Gly1046Ser (c.3136G>A)?

BLM p.Gly1046Ser (c.3136G>A) is associated with hereditary neoplastic syndrome, Bloom syndrome (ClinVar).

How common is BLM p.Gly1046Ser (c.3136G>A) in the general population?

BLM p.Gly1046Ser (c.3136G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about BLM p.Gly1046Ser (c.3136G>A)?

AlphaMissense predicts ambiguous (score 0.36) — an in-silico prediction, not a clinical call.

BLM p.Gly1046Ser

c.3136G>A · rs373241803 · VCV1019545

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.36 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.36	ambiguous
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -10.33	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	28.1	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 0.0107% African / African-American · 8/74,810 alleles

Filtering AF 0.00529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00056% 9/1,606,786 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,351
Remaining individualsnot grpmax-eligible	0.00161%	62,094

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.Gly1046Ser
Coding: c.3136G>A
MANE Select: NM_000057
dbSNP: rs373241803
Type: single nucleotide variant
Location: chr15:90794283 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 61.10 · 16 PDB

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.Gly1046Arg Uncertain significance ★ ⚠ same residue
BLM p.Gly1046Val 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

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-gly1046ser (accessed [today's date]).

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