Is HAAO p.Trp186Ter (c.558G>A) pathogenic?

HAAO p.Trp186Ter (c.558G>A) is classified Pathogenic in HAAO (ClinVar, Multiple submitters, 3 submitters; last evaluated 2018-04-16). Absent from gnomAD v4.1; Associated with vertebral, cardiac, renal, and limb defects syndrome 1.

What condition is associated with HAAO p.Trp186Ter (c.558G>A)?

HAAO p.Trp186Ter (c.558G>A) is associated with vertebral, cardiac, renal, and limb defects syndrome 1 (ClinVar).

How common is HAAO p.Trp186Ter (c.558G>A) in the general population?

HAAO p.Trp186Ter (c.558G>A) is absent from gnomAD v4.1 (gnomAD).

HAAO p.Trp186Ter

c.558G>A · rs1135401743 · VCV403728

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

vertebral, cardiac, renal, and limb defects syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.3, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HAAO
Protein: p.Trp186Ter
Coding: c.558G>A
MANE Select: NM_012205
dbSNP: rs1135401743
Type: single nucleotide variant
Location: chr2:42769785 (GRCh38)
Gene constraint: LOEUF 1.544 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.95 · 3 PDB
Residue 186: a UniProt-annotated variant site (in vcrl1; strongly reduced 3-hydroxyanthranilate 3,4-dioxygenase activity in vitro); the 'domain b' region; an α-helix

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

Disease context

vertebral, cardiac, renal, and limb defects syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HAAO p.Arg175Pro Uncertain significance ★★ ⚠ same condition
HAAO c.440+19C>T Benign ★★ same condition
HAAO c.630+34C>T Benign ★★ same condition
HAAO c.81-10C>T Benign ★★ same condition
HAAO p.Ile37Val Benign ★★ same condition
HAAO p.Thr42Ser Benign ★★ same condition
HAAO c.243+1G>A Likely pathogenic ★ same condition
HAAO c.630+2T>A 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/haao-p-trp186ter (accessed [today's date]).

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