Is HMBS p.Val202= (c.606G>T) pathogenic?

HMBS p.Val202= (c.606G>T) is classified Benign/Likely benign in HMBS (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 28.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with acute intermittent porphyria.

What condition is associated with HMBS p.Val202= (c.606G>T)?

HMBS p.Val202= (c.606G>T) is associated with acute intermittent porphyria (ClinVar).

How is Acute intermittent porphyria inherited?

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

HMBS p.Val202=

Q: How common is HMBS p.Val202= (c.606G>T) in the general population?

HMBS p.Val202= (c.606G>T) is common (popmax 28.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.606G>T · rs1131488 · VCV255485

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 28.4%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

acute intermittent porphyria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.84 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP -1.3, phastCons 1
Overall
CADD	7.102	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 28.4% European (non-Finnish) · 324,450/1,142,362 alleles

Filtering AF 28.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.3%

Overall 26.6% 411,378/1,546,376 alleles · common exomes 375,557/1,394,170 · genomes 35,821/152,206 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	34.8%	3
Amishnot grpmax-eligible	31.3%	3
European (non-Finnish)grpmax	28.4%	4
Middle Eastern	27.4%	4
Remaining individualsnot grpmax-eligible	26.4%	4
Finnishnot grpmax-eligible	25.3%	4
South Asian	19.9%	5
Admixed American	17.2%	6
African / African-American	16.5%	6
East Asian	16%	6

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val202=
Coding: c.606G>T
MANE Select: NM_000190
dbSNP: rs1131488
Type: single nucleotide variant
Location: chr11:119091520 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 202: a UniProt-annotated variant site (in aip)

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.Val202Leu 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
HMBS c.913-1G>A Pathogenic ★★ same condition
HMBS p.Ala331Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
HMBS p.Arg116Trp 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-val202 (accessed [today's date]).

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