Is DHDDS p.Lys42Glu (c.124A>G) pathogenic?

DHDDS p.Lys42Glu (c.124A>G) is classified Pathogenic in DHDDS (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-07-19). AlphaMissense: ambiguous (0.4687); Very rare (popmax 0.0022%, nfe); Associated with DHDDS-related disorders.

What condition is associated with DHDDS p.Lys42Glu (c.124A>G)?

DHDDS p.Lys42Glu (c.124A>G) is associated with DHDDS-related disorders, retinitis pigmentosa 59, retinitis pigmentosa (ClinVar).

How common is DHDDS p.Lys42Glu (c.124A>G) in the general population?

DHDDS p.Lys42Glu (c.124A>G) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about DHDDS p.Lys42Glu (c.124A>G)?

AlphaMissense predicts ambiguous (score 0.4687) — an in-silico prediction, not a clinical call.

DHDDS p.Lys42Glu

c.124A>G · rs147394623 · VCV30709

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

ambiguous

0.4687 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

DHDDS-related disorders

Computational evidence

Protein change
AlphaMissense	0.4687	ambiguous
REVEL	0.67	pathogenic-leaning
SaProt	LLR -10.89	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 9,886 bp · p 3.6e-06 · regional, not allelic
Overall
CADD	27.5	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 0.0022% European (non-Finnish) · 26/1,179,950 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.0128% 207/1,613,994 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.544%	184
Remaining individualsnot grpmax-eligible	0.0304%	3,288
European (non-Finnish)grpmax	0.0022%	45,383
Admixed American	0.00167%	60,008

Ashkenazi Jewish 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.Lys42Glu
Coding: c.124A>G
MANE Select: NM_205861
dbSNP: rs147394623
Type: single nucleotide variant
Location: chr1:26438228 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 95.01 · 9 PDB
Residue 42: a UniProt-annotated variant site (in rp59; 5-fold reduction in catalytic activity and reduced affinity for fpp but not for ipp); an α-helix

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

Disease context

DHDDS-related disorders

Also linked: retinitis pigmentosa 59 retinitis pigmentosa developmental delay and seizures with or without movement abnormalities

Similar variants

DHDDS p.Lys42Ter Likely pathogenic ★ same residue
DHDDS p.Lys42Arg Uncertain significance ★ ⚠ same residue
DHDDS p.Lys42= 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-lys42glu (accessed [today's date]).

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