Is BLM p.Ser1228Phe (c.3683C>T) pathogenic?

BLM p.Ser1228Phe (c.3683C>T) is classified Uncertain significance in BLM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). AlphaMissense: likely benign (0.1291); Absent from gnomAD v4.1; Associated with Bloom syndrome.

What condition is associated with BLM p.Ser1228Phe (c.3683C>T)?

BLM p.Ser1228Phe (c.3683C>T) is associated with Bloom syndrome (ClinVar).

How common is BLM p.Ser1228Phe (c.3683C>T) in the general population?

BLM p.Ser1228Phe (c.3683C>T) is absent from gnomAD v4.1 (gnomAD).

How is Bloom syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BLM p.Ser1228Phe (c.3683C>T)?

AlphaMissense predicts likely benign (score 0.1291) — an in-silico prediction, not a clinical call.

BLM p.Ser1228Phe

c.3683C>T · rs1897236482 · VCV2860183

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1291 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bloom syndrome

Computational evidence

Protein change
AlphaMissense	0.1291	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -11.09	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 46 kb · p 0.035 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BLM
Protein: p.Ser1228Phe
Coding: c.3683C>T
MANE Select: NM_000057
dbSNP: rs1897236482
Type: single nucleotide variant
Location: chr15:90804291 (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 1228: the 'necessary for ssdna and dna holliday junction binding' region; an α-helix; the hrdc domain

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

Disease context

Bloom syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Bloom syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Specific population)

Similar variants

BLM p.Ser1228Tyr Uncertain significance ★★ ⚠ same residue
BLM p.Ser1228Cys Uncertain significance ★ ⚠ same residue
BLM p.Ser1228fs Pathogenic ★ same residue
BLM p.Ser1228= Likely benign ★ 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-ser1228phe (accessed [today's date]).

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