Is DHDDS p.Asp189Asn (c.565G>A) pathogenic?

DHDDS p.Asp189Asn (c.565G>A) is classified Conflicting classifications of pathogenicity in DHDDS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.1878); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with DHDDS p.Asp189Asn (c.565G>A)?

DHDDS p.Asp189Asn (c.565G>A) is associated with Inborn genetic diseases, retinitis pigmentosa 59, inherited retinal dystrophy (ClinVar).

How common is DHDDS p.Asp189Asn (c.565G>A) in the general population?

DHDDS p.Asp189Asn (c.565G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about DHDDS p.Asp189Asn (c.565G>A)?

AlphaMissense predicts likely benign (score 0.1878) — an in-silico prediction, not a clinical call.

DHDDS p.Asp189Asn

c.565G>A · rs748833924 · VCV1352776

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1878 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1878	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 26 kb · p 0.063 · regional, not allelic
Overall
CADD	22.7	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 0.0133% Admixed American · 8/59,964 alleles

Filtering AF 0.00791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00744%

Overall 0.00793% 128/1,613,626 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.548%	182
Admixed Americangrpmax	0.0133%	7,496
European (non-Finnish)	0.00941%	10,629
Remaining individualsnot grpmax-eligible	0.0048%	20,823
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

Amish 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: DHDDS
Protein: p.Asp189Asn
Coding: c.565G>A
MANE Select: NM_205861
dbSNP: rs748833924
Type: single nucleotide variant
Location: chr1:26457813 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 95.01 · 9 PDB
Residue 189: a UniProt-annotated variant site (in rp59; in a patient with congenital disorder of glycosylation); an α-helix

Full DHDDS 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

Also linked: retinitis pigmentosa 59 inherited retinal dystrophy

Similar variants

DHDDS p.Asp189Gly Uncertain significance ★★ ⚠ same residue
DHDDS p.Asp189His Uncertain significance ★★ ⚠ same residue
DHDDS p.Asp189= Likely benign ★ same residue
DHDDS c.658-2A>G Likely pathogenic ★★ same condition
DHDDS p.Arg205Gln Pathogenic ★★ same condition
DHDDS p.Arg211Gln Pathogenic ★★ same condition
DHDDS p.Arg37Cys Pathogenic ★★ same condition
DHDDS p.Arg37His 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/dhdds-p-asp189asn (accessed [today's date]).

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