Is HMBS p.Arg173Pro (c.518G>C) pathogenic?

HMBS p.Arg173Pro (c.518G>C) is classified Pathogenic in HMBS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely pathogenic (0.9933); Absent from gnomAD v4.1; Associated with acute intermittent porphyria.

What condition is associated with HMBS p.Arg173Pro (c.518G>C)?

HMBS p.Arg173Pro (c.518G>C) is associated with acute intermittent porphyria (ClinVar).

How common is HMBS p.Arg173Pro (c.518G>C) in the general population?

HMBS p.Arg173Pro (c.518G>C) is absent from gnomAD v4.1 (gnomAD).

How is Acute intermittent porphyria inherited?

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

What do computational predictors say about HMBS p.Arg173Pro (c.518G>C)?

AlphaMissense predicts likely pathogenic (score 0.9933) — an in-silico prediction, not a clinical call.

HMBS p.Arg173Pro

c.518G>C · rs118204096 · VCV2582784

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9933 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acute intermittent porphyria

Computational evidence

Protein change
AlphaMissense	0.9933	likely pathogenic ✓ concordant with ClinVar · top 8% in HMBS
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -13.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,246 bp · p 0.0046 · regional, not allelic
Overall
CADD	33.0	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: HMBS
Protein: p.Arg173Pro
Coding: c.518G>C
MANE Select: NM_000190
dbSNP: rs118204096
Type: single nucleotide variant
Location: chr11:119091432 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 173: an α-helix; a UniProt-annotated variant site (in aip; less than 1% of wild-type activity); a UniProt-annotated variant site (in aip; loss of hydroxymethylbilane synthase activity; 1% of wild-type activity; lower thermal stability than wild-type enzyme)

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.Arg173Gln Pathogenic ★★ same residue
HMBS p.Arg173Trp Pathogenic/Likely pathogenic ★★ 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
HMBS p.Ala331Val Pathogenic/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/hmbs-p-arg173pro (accessed [today's date]).

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