Is HMBS p.Ala331Val (c.992C>T) pathogenic?

HMBS p.Ala331Val (c.992C>T) is classified Pathogenic/Likely pathogenic in HMBS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.7842); Very rare (popmax 0.00267%, afr); Associated with acute intermittent porphyria.

What condition is associated with HMBS p.Ala331Val (c.992C>T)?

HMBS p.Ala331Val (c.992C>T) is associated with acute intermittent porphyria (ClinVar).

How common is HMBS p.Ala331Val (c.992C>T) in the general population?

HMBS p.Ala331Val (c.992C>T) is very rare (popmax 0.00267%, afr) (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.Ala331Val (c.992C>T)?

AlphaMissense predicts likely pathogenic (score 0.7842) — an in-silico prediction, not a clinical call.

HMBS p.Ala331Val

c.992C>T · rs770086296 · VCV851744

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7842 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acute intermittent porphyria

Computational evidence

Protein change
AlphaMissense	0.7842	likely pathogenic ✓ concordant with ClinVar
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,246 bp · p 0.0046 · regional, not allelic
Overall
CADD	28.2	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

Grpmax group 0.00267% African / African-American · 2/74,922 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00118% 19/1,614,060 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,240
African / African-Americangrpmax	0.00267%	37,461
Admixed American	0.00167%	60,006
European (non-Finnish)	0.00119%	84,287

Remaining individuals 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.Ala331Val
Coding: c.992C>T
MANE Select: NM_000190
dbSNP: rs770086296
Type: single nucleotide variant
Location: chr11:119093189 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 331: a UniProt-annotated variant site (in aip); 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 p.Ala331= Likely benign ★ 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.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-ala331val (accessed [today's date]).

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