Is HMBS p.Pro241= (c.723C>T) pathogenic?

HMBS p.Pro241= (c.723C>T) is classified Benign/Likely benign in HMBS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-18). Ultra-rare (popmax 0.0703%, sas); Associated with acute intermittent porphyria.

What condition is associated with HMBS p.Pro241= (c.723C>T)?

HMBS p.Pro241= (c.723C>T) is associated with acute intermittent porphyria (ClinVar).

How common is HMBS p.Pro241= (c.723C>T) in the general population?

HMBS p.Pro241= (c.723C>T) is ultra-rare (popmax 0.0703%, sas) (gnomAD).

How is Acute intermittent porphyria inherited?

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

HMBS p.Pro241=

c.723C>T · rs202067277 · VCV302733

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0703%, 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 -8.2	GERP -4.3
Overall
CADD	0.398	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0703% South Asian · 64/91,076 alleles

Filtering AF 0.0565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.0209% 338/1,614,146 alleles · ultra-rare exomes 316/1,461,868 · genomes 22/152,278 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0703%	1,423
European (non-Finnish)	0.0215%	4,646
Remaining individualsnot grpmax-eligible	0.016%	6,251
African / African-American	0.012%	8,337
Admixed American	0.00167%	60,012

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.Pro241=
Coding: c.723C>T
MANE Select: NM_000190
dbSNP: rs202067277
Type: single nucleotide variant
Location: chr11:119092475 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 241: an α-helix

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-pro241 (accessed [today's date]).

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