Is HMBS p.Arg19fs (c.57_58del) pathogenic?

HMBS p.Arg19fs (c.5758del) is classified Pathogenic in HMBS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-05). Very rare (popmax 0.00134%, afr).

How common is HMBS p.Arg19fs (c.57_58del) in the general population?

HMBS p.Arg19fs (c.57_58del) is very rare (popmax 0.00134%, afr) (gnomAD).

HMBS p.Arg19fs

c.57_58del · rs1034391830 · VCV1073693

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

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 2 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Overall
CADD	34.0	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 0.00134% African / African-American · 1/74,884 alleles

Overall 6.2e-05% 1/1,613,888 alleles · very rare exomes 0/1,461,804 · genomes 1/152,084 · joint denominator

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: HMBS
Protein: p.Arg19fs
Coding: c.57_58del
MANE Select: NM_000190
dbSNP: rs1034391830
Type: Microsatellite
Location: chr11:119088275 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 19: an α-helix

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

Similar variants

HMBS p.Arg19Thr Uncertain significance ★ ⚠ same residue
HMBS p.Gln314fs Pathogenic/Likely pathogenic ★★ same type
HMBS c.267-3_267-2del Uncertain significance ★★ same type
HMBS c.825+3_825+6del Uncertain significance ★★ same type
HMBS c.772-10_772-8del Likely pathogenic ★ same type
HMBS p.Gly281del Likely pathogenic ★ same type
HMBS p.Leu244fs Pathogenic ★ same type
HMBS p.Ser75fs Pathogenic ★ same type

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-arg19fs (accessed [today's date]).

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