Is HMBS p.Asp178= (c.534C>T) pathogenic?

HMBS p.Asp178= (c.534C>T) is classified Likely benign in HMBS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-13). Ultra-rare (popmax 0.0465%, afr); Associated with Inborn genetic diseases.

What condition is associated with HMBS p.Asp178= (c.534C>T)?

HMBS p.Asp178= (c.534C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HMBS p.Asp178= (c.534C>T) in the general population?

HMBS p.Asp178= (c.534C>T) is ultra-rare (popmax 0.0465%, afr) (gnomAD).

HMBS p.Asp178=

c.534C>T · rs766554554 · VCV746326

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0465%, afr)

Conditions

Inborn genetic diseases

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 -5.7	GERP -4.5
Overall
CADD	8.724	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0465% African / African-American · 34/73,048 alleles

Filtering AF 0.0342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00773% 120/1,551,618 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0465%	2,148
Admixed American	0.0157%	6,373
Remaining individualsnot grpmax-eligible	0.00666%	15,024
European (non-Finnish)	0.00619%	16,155
East Asian	0.00244%	40,942
Finnishnot grpmax-eligible	0.00167%	59,900
South Asian	0.00119%	84,066

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.Asp178=
Coding: c.534C>T
MANE Select: NM_000190
dbSNP: rs766554554
Type: single nucleotide variant
Location: chr11:119091448 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.81 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 90.54 · 11 PDB
Residue 178: an α-helix; a UniProt-annotated variant site (in aip; uncertain significance; slightly decreased hydroxymethylbilane synthase activity corresponding to 80% of wild-type activity)

Full HMBS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HMBS p.Asp178Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
HMBS c.499-17T>G Uncertain significance ★★ same condition
HMBS p.Glu258Asp Uncertain significance ★★ ⚠ same condition
HMBS p.Trp198Cys Uncertain significance ★★ ⚠ same condition
HMBS p.Val143Met Uncertain significance ★★ ⚠ same condition
HMBS p.Pro127Gln Likely benign ★★ ⚠ same condition
HMBS p.Ala8Thr Uncertain significance ★ ⚠ same condition
HMBS p.Asn322Asp Uncertain significance ★ ⚠ 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-asp178 (accessed [today's date]).

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