Is HMBS p.Pro101= (c.303C>T) pathogenic?

HMBS p.Pro101= (c.303C>T) is classified Benign in HMBS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-22). Low-frequency (popmax 1.41%, sas); Associated with acute intermittent porphyria.

What condition is associated with HMBS p.Pro101= (c.303C>T)?

HMBS p.Pro101= (c.303C>T) is associated with acute intermittent porphyria (ClinVar).

How common is HMBS p.Pro101= (c.303C>T) in the general population?

HMBS p.Pro101= (c.303C>T) is low-frequency (popmax 1.41%, sas) (gnomAD).

How is Acute intermittent porphyria inherited?

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

HMBS p.Pro101=

c.303C>T · rs139147408 · VCV302728

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.41%, sas)

Conditions

acute intermittent porphyria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP -0.96, phastCons 0.98
Overall
CADD	10.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.41% South Asian · 1,279/90,962 alleles

Filtering AF 1.34% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.32%

Overall 0.084% 1,356/1,613,740 alleles · low-frequency exomes 1,279/1,461,476 · genomes 77/152,264 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.41%	71
Remaining individualsnot grpmax-eligible	0.096%	1,042
Middle Eastern	0.0495%	2,020
East Asian	0.00668%	14,959
African / African-American	0.00267%	37,503
European (non-Finnish)	0.000763%	131,091

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.Pro101=
Coding: c.303C>T
MANE Select: NM_000190
dbSNP: rs139147408
Type: single nucleotide variant
Location: chr11:119089719 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB

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 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
HMBS p.Arg116Trp Pathogenic/Likely pathogenic ★★ same condition
HMBS p.Arg149Ter 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-pro101 (accessed [today's date]).

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