Is DHDDS p.Gly92Arg (c.274G>A) pathogenic?

DHDDS p.Gly92Arg (c.274G>A) is classified Uncertain significance in DHDDS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-09). AlphaMissense: likely pathogenic (0.9028); Ultra-rare (popmax 0.0165%, mid); Associated with retinitis pigmentosa 59.

What condition is associated with DHDDS p.Gly92Arg (c.274G>A)?

DHDDS p.Gly92Arg (c.274G>A) is associated with retinitis pigmentosa 59 (ClinVar).

How common is DHDDS p.Gly92Arg (c.274G>A) in the general population?

DHDDS p.Gly92Arg (c.274G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DHDDS p.Gly92Arg (c.274G>A)?

AlphaMissense predicts likely pathogenic (score 0.9028) — an in-silico prediction, not a clinical call.

DHDDS p.Gly92Arg

c.274G>A · rs766371067 · VCV1022103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

retinitis pigmentosa 59

Computational evidence

Protein change
AlphaMissense	0.9028	likely pathogenic
REVEL	0.678	pathogenic-leaning
SaProt	LLR -12.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 9,886 bp · p 3.6e-06 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000821% 12/1,461,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,508
South Asian	0.0011%	91,068
European (non-Finnish)	0.000763%	131,115

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.Gly92Arg
Coding: c.274G>A
MANE Select: NM_205861
dbSNP: rs766371067
Type: single nucleotide variant
Location: chr1:26442824 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 95.01 · 9 PDB
Residue 92: 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

retinitis pigmentosa 59 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
DHDDS p.Arg37Ser Pathogenic ★★ same condition
DHDDS p.Gly35Glu Pathogenic/Likely pathogenic ★★ same condition
DHDDS p.Lys42Glu 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-gly92arg (accessed [today's date]).

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