Is HPD p.Ser54fs (c.158dup) pathogenic?

HPD p.Ser54fs (c.158dup) is classified Pathogenic in HPD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-10-01). Very rare (popmax 0.00167%, amr); Associated with tyrosinemia type III.

What condition is associated with HPD p.Ser54fs (c.158dup)?

HPD p.Ser54fs (c.158dup) is associated with tyrosinemia type III, hawkinsinuria (ClinVar).

How common is HPD p.Ser54fs (c.158dup) in the general population?

HPD p.Ser54fs (c.158dup) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Tyrosinemia type 3 inherited?

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

HPD p.Ser54fs

c.158dup · rs895823217 · VCV642856

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

tyrosinemia type III

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.9	GERP -4.2
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,992 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000558% 9/1,613,980 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,244
Admixed Americangrpmax	0.00167%	59,992
European (non-Finnish)	0.000508%	196,660

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: HPD
Protein: p.Ser54fs
Coding: c.158dup
MANE Select: NM_002150
dbSNP: rs895823217
Type: Duplication
Location: chr12:121857367 (GRCh38)
Gene constraint: LOEUF 0.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.00 · 4 PDB
Residue 54: the voc 1 domain

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

Disease context

tyrosinemia type III — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hawkinsinuria

For Tyrosinemia type 3 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

HPD p.Glu124Ter Likely pathogenic ★ same condition
HPD p.Glu148fs Pathogenic ★ same condition
HPD p.Ile62fs Pathogenic ★ same condition
HPD c.519-20_519-19dup Likely benign ★ same condition
HPD p.Arg225Ter Pathogenic/Likely pathogenic ★★ same condition
HPD p.Gln205Ter Pathogenic/Likely pathogenic ★★ same condition
HPD p.Tyr160Cys Likely pathogenic ★★ same condition
HPD p.Ala230Thr Uncertain significance ★★ ⚠ 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/hpd-p-ser54fs (accessed [today's date]).

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