Is DHDDS p.Arg47Leu (c.140G>T) pathogenic?

DHDDS p.Arg47Leu (c.140G>T) is classified Uncertain significance in DHDDS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: ambiguous (0.4609); Very rare (popmax 0.000254%, nfe).

How common is DHDDS p.Arg47Leu (c.140G>T) in the general population?

DHDDS p.Arg47Leu (c.140G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DHDDS p.Arg47Leu (c.140G>T)?

AlphaMissense predicts ambiguous (score 0.4609) — an in-silico prediction, not a clinical call.

DHDDS p.Arg47Leu

c.140G>T · VCV4963160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4609 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4609	ambiguous
REVEL	0.418	indeterminate
SaProt	LLR -5.58	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP 1, phastCons 0.12
Regional constraint	o/e 0.58	unconstrained · MANE · 9,886 bp · p 3.6e-06 · regional, not allelic
Overall
CADD	21.3	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 0.000254% European (non-Finnish) · 3/1,179,944 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,034 alleles · very rare exomes 3/1,461,694 · genomes 0/152,340 · joint denominator

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.Arg47Leu
Coding: c.140G>T
MANE Select: NM_205861
Type: single nucleotide variant
Location: chr1:26438244 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 95.01 · 9 PDB
Residue 47: an α-helix

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

Similar variants

DHDDS p.Arg47Trp Uncertain significance ★★ same residue
DHDDS p.Arg47Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DHDDS p.Arg47= Likely benign ★ same residue
DHDDS c.658-2A>G Likely pathogenic ★★ same type
DHDDS p.Arg205Gln Pathogenic ★★ same type
DHDDS p.Arg211Gln Pathogenic ★★ same type
DHDDS p.Arg37Cys Pathogenic ★★ same type
DHDDS p.Arg37His Pathogenic/Likely pathogenic ★★ same type

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-arg47leu (accessed [today's date]).

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