Is DHDDS p.Leu254Pro (c.761T>C) pathogenic?

DHDDS p.Leu254Pro (c.761T>C) is classified Uncertain significance in DHDDS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.8844); Ultra-rare (popmax 0.0822%, mid); Associated with Inborn genetic diseases.

What condition is associated with DHDDS p.Leu254Pro (c.761T>C)?

DHDDS p.Leu254Pro (c.761T>C) is associated with Inborn genetic diseases, retinitis pigmentosa 59, inherited retinal dystrophy (ClinVar).

How common is DHDDS p.Leu254Pro (c.761T>C) in the general population?

DHDDS p.Leu254Pro (c.761T>C) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about DHDDS p.Leu254Pro (c.761T>C)?

AlphaMissense predicts likely pathogenic (score 0.8844) — an in-silico prediction, not a clinical call.

DHDDS p.Leu254Pro

c.761T>C · rs755439760 · VCV1690716

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8844 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8844	likely pathogenic
REVEL	0.558	indeterminate
SaProt	LLR -16.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 26 kb · p 0.063 · regional, not allelic
Overall
CADD	25.4	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 0.0822% Middle Eastern · 5/6,082 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00378% 61/1,612,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,216
Admixed American	0.025%	4,000
Remaining individualsnot grpmax-eligible	0.00481%	20,811
African / African-American	0.00401%	24,955
European (non-Finnish)	0.00288%	34,678
Finnishnot grpmax-eligible	0.00156%	64,036

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.Leu254Pro
Coding: c.761T>C
MANE Select: NM_205861
dbSNP: rs755439760
Type: single nucleotide variant
Location: chr1:26460140 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 95.01 · 9 PDB
Residue 254: 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 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.Arg38His Pathogenic/Likely pathogenic ★★ same condition
DHDDS p.Gly35Glu 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-leu254pro (accessed [today's date]).

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