Is DHDDS p.Gln228His (c.684A>C) pathogenic?

DHDDS p.Gln228His (c.684A>C) is classified Uncertain significance in DHDDS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-01). AlphaMissense: likely pathogenic (0.6); Very rare (popmax 0.00446%, eas); Associated with inherited retinal dystrophy.

What condition is associated with DHDDS p.Gln228His (c.684A>C)?

DHDDS p.Gln228His (c.684A>C) is associated with inherited retinal dystrophy (ClinVar).

How common is DHDDS p.Gln228His (c.684A>C) in the general population?

DHDDS p.Gln228His (c.684A>C) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about DHDDS p.Gln228His (c.684A>C)?

AlphaMissense predicts likely pathogenic (score 0.6) — an in-silico prediction, not a clinical call.

DHDDS p.Gln228His

c.684A>C · rs766651316 · VCV3028672

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.6	likely pathogenic
REVEL	0.459	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.023	GERP -3.7, phastCons 0.1
Regional constraint	o/e 0.89	unconstrained · MANE · 26 kb · p 0.063 · regional, not allelic
Overall
CADD	16.71	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 0.00446% East Asian · 2/44,884 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,878 alleles · very rare

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.Gln228His
Coding: c.684A>C
MANE Select: NM_205861
dbSNP: rs766651316
Type: single nucleotide variant
Location: chr1:26460063 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 95.01 · 9 PDB
Residue 228: a UniProt-annotated variant site (in rp59; in a patient with congenital disorder of glycosylation); a β-strand

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

Similar variants

DHDDS p.Gln228= Likely benign ★ same residue
DHDDS p.Ala77Thr Uncertain significance ★★ ⚠ same condition
DHDDS p.Arg327Cys Uncertain significance ★★ ⚠ same condition
DHDDS p.Asp123Asn Uncertain significance ★★ ⚠ same condition
DHDDS p.Asp323Glu Uncertain significance ★★ ⚠ same condition
DHDDS p.Leu254Pro Uncertain significance ★★ ⚠ same condition
DHDDS p.Leu286Ile Uncertain significance ★★ ⚠ same condition
DHDDS p.Lys84Arg Uncertain significance ★★ ⚠ 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-gln228his (accessed [today's date]).

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