Is HMBS p.Ser75fs (c.219_220del) pathogenic?

HMBS p.Ser75fs (c.219220del) is classified Pathogenic in HMBS (ClinVar, Single submitter, 2 submitters; last evaluated 2019-03-08). Absent from gnomAD; Associated with acute intermittent porphyria.

What condition is associated with HMBS p.Ser75fs (c.219_220del)?

HMBS p.Ser75fs (c.219_220del) is associated with acute intermittent porphyria (ClinVar).

How common is HMBS p.Ser75fs (c.219_220del) in the general population?

HMBS p.Ser75fs (c.219_220del) is absent from gnomAD (gnomAD).

How is Acute intermittent porphyria inherited?

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

HMBS p.Ser75fs

c.219_220del · rs1592214498 · VCV653427

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

acute intermittent porphyria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 5 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HMBS
Protein: p.Ser75fs
Coding: c.219_220del
MANE Select: NM_000190
dbSNP: rs1592214498
Type: Microsatellite
Location: chr11:119089221 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 75: an α-helix

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

Disease context

acute intermittent porphyria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Acute intermittent porphyria (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

HMBS p.Gln314fs Pathogenic/Likely pathogenic ★★ same condition
HMBS p.Leu244fs Pathogenic ★ same condition
HMBS p.Ser75Asn Uncertain significance ★ ⚠ same residue
HMBS c.160+5G>C Pathogenic/Likely pathogenic ★★ same condition
HMBS c.345-1G>A Pathogenic ★★ same condition
HMBS c.613-1G>A Pathogenic ★★ same condition
HMBS c.826-2A>T Pathogenic/Likely pathogenic ★★ same condition
HMBS c.913-1G>A 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/hmbs-p-ser75fs (accessed [today's date]).

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