Is HMBS p.Arg167Pro (c.500G>C) pathogenic?

HMBS p.Arg167Pro (c.500G>C) is classified Pathogenic/Likely pathogenic in HMBS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-08). AlphaMissense: likely pathogenic (0.9956); Absent from gnomAD v4.1; Associated with acute intermittent porphyria.

What condition is associated with HMBS p.Arg167Pro (c.500G>C)?

HMBS p.Arg167Pro (c.500G>C) is associated with acute intermittent porphyria, encephalopathy, porphyria-related, leukoencephalopathy, porphyria-related (ClinVar).

How common is HMBS p.Arg167Pro (c.500G>C) in the general population?

HMBS p.Arg167Pro (c.500G>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.Arg167Pro (c.500G>C)?

AlphaMissense predicts likely pathogenic (score 0.9956) — an in-silico prediction, not a clinical call.

HMBS p.Arg167Pro

c.500G>C · rs118204095 · VCV1509204

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9956 · 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	0.9956	likely pathogenic ✓ concordant with ClinVar · top 6% in HMBS
REVEL	0.95	strongly pathogenic-leaning
SaProt	LLR -14.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.80 · evaluated, not missing
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	34.0	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.Arg167Pro
Coding: c.500G>C
MANE Select: NM_000190
dbSNP: rs118204095
Type: single nucleotide variant
Location: chr11:119091414 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 167: a UniProt-annotated variant site (in aip, encep and lencep; decreased hydroxymethylbilane synthase activity due to defective enzyme-intermediate complexes turnover and regeneration of free enzyme molecules); a UniProt-annotated variant site (in aip and encep; severely decreased hydroxymethylbilane synthase activity; results in less than 5% of wild-type activity; 2-fold decrease of vmax; 33-fold increase of km)

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

Also linked: encephalopathy, porphyria-related leukoencephalopathy, porphyria-related

For Acute intermittent porphyria (Orphanet):

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

Similar variants

HMBS p.Arg167Gln Pathogenic/Likely pathogenic ★★ same residue
HMBS p.Arg167Trp Pathogenic ★★ same residue
HMBS p.Arg167Leu Pathogenic same residue
HMBS p.Arg167Gly 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

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-arg167pro (accessed [today's date]).

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