Is DHDDS p.Val253Met (c.757G>A) pathogenic?

DHDDS p.Val253Met (c.757G>A) is classified Benign in DHDDS (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.078); Common (popmax 74.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with developmental delay and seizures with or without movement abnormalities.

What do computational predictors say about DHDDS p.Val253Met (c.757G>A)?

AlphaMissense predicts likely benign (score 0.078) — an in-silico prediction, not a clinical call.

DHDDS p.Val253Met

Q: What condition is associated with DHDDS p.Val253Met (c.757G>A)?

DHDDS p.Val253Met (c.757G>A) is associated with developmental delay and seizures with or without movement abnormalities, retinitis pigmentosa 59, inherited retinal dystrophy (ClinVar).

Q: How common is DHDDS p.Val253Met (c.757G>A) in the general population?

DHDDS p.Val253Met (c.757G>A) is common (popmax 74.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.757G>A · rs3816539 · VCV297075

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.078 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 74.9%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental delay and seizures with or without movement abnormalities

Computational evidence

Protein change
AlphaMissense	0.078	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -7.07	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 0.29	GERP -3.4, phastCons 0.001
Regional constraint	o/e 0.89	unconstrained · MANE · 26 kb · p 0.063 · regional, not allelic
Overall
CADD	13.5	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 74.9% East Asian · 33,567/44,840 alleles

Filtering AF 74.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 73.9%

Overall 25.3% 408,172/1,611,146 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	74.9%	1
African / African-American	45.2%	2
South Asian	40.3%	2
Amishnot grpmax-eligible	28.3%	4
Admixed American	28.3%	4
Remaining individualsnot grpmax-eligible	27.4%	4
Middle Eastern	25.4%	4
Finnishnot grpmax-eligible	24.4%	4
European (non-Finnish)	20.9%	5
Ashkenazi Jewishnot grpmax-eligible	20.8%	5

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.Val253Met
Coding: c.757G>A
MANE Select: NM_205861
dbSNP: rs3816539
Type: single nucleotide variant
Location: chr1:26460136 (GRCh38)
Gene constraint: LOEUF 0.536 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 95.01 · 9 PDB
Residue 253: a UniProt-annotated variant site (in rp59; in a patient with congenital disorder of glycosylation); a UniProt-annotated variant site (in); an α-helix

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

Disease context

developmental delay and seizures with or without movement abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinitis pigmentosa 59 inherited retinal dystrophy retinitis pigmentosa

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-val253met (accessed [today's date]).

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