Is DHDDS p.Ser303Leu (c.908C>T) pathogenic?

DHDDS p.Ser303Leu (c.908C>T) is classified Conflicting classifications of pathogenicity in DHDDS (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0714); Ultra-rare (popmax 0.0111%, eas); Associated with inherited retinal dystrophy.

What condition is associated with DHDDS p.Ser303Leu (c.908C>T)?

DHDDS p.Ser303Leu (c.908C>T) is associated with inherited retinal dystrophy, retinitis pigmentosa 59, retinitis pigmentosa (ClinVar).

How common is DHDDS p.Ser303Leu (c.908C>T) in the general population?

DHDDS p.Ser303Leu (c.908C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about DHDDS p.Ser303Leu (c.908C>T)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

DHDDS p.Ser303Leu

c.908C>T · rs141852437 · VCV729971

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -4.96	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 0.12	GERP 0.7, phastCons 0.014
Regional constraint	o/e 0.89	unconstrained · MANE · 26 kb · p 0.063 · regional, not allelic
Overall
CADD	17.82	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 0.0111% East Asian · 5/44,894 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.0263% 424/1,613,914 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.979%	102
Remaining individualsnot grpmax-eligible	0.0816%	1,225
East Asiangrpmax	0.0111%	8,979
European (non-Finnish)	0.00627%	15,947
African / African-American	0.00534%	18,736

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.Ser303Leu
Coding: c.908C>T
MANE Select: NM_205861
dbSNP: rs141852437
Type: single nucleotide variant
Location: chr1:26469037 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 95.01 · 9 PDB
Residue 303: 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

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 59 retinitis pigmentosa

Similar variants

DHDDS p.Ser303Pro Uncertain significance ★ ⚠ same residue
DHDDS p.Ser303= 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
DHDDS p.Arg37Ser 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-ser303leu (accessed [today's date]).

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