Is DDHD1 p.Asp228= (c.684T>C) pathogenic?

DDHD1 p.Asp228= (c.684T>C) is classified Conflicting classifications of pathogenicity in DDHD1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-09-20). Very rare (popmax 0.00017%, nfe); Associated with hereditary spastic paraplegia 28.

What condition is associated with DDHD1 p.Asp228= (c.684T>C)?

DDHD1 p.Asp228= (c.684T>C) is associated with hereditary spastic paraplegia 28, hereditary spastic paraplegia (ClinVar).

How common is DDHD1 p.Asp228= (c.684T>C) in the general population?

DDHD1 p.Asp228= (c.684T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Autosomal recessive spastic paraplegia type 28 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DDHD1 p.Asp228=

c.684T>C · rs1382953265 · VCV1344295

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

hereditary spastic paraplegia 28

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.7	GERP -2.9
Overall
CADD	3.038	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,938 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,550 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: DDHD1
Protein: p.Asp228=
Coding: c.684T>C
MANE Select: NM_001160148
dbSNP: rs1382953265
Type: single nucleotide variant
Location: chr14:53152415 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.11
Residue 228: the 'disordered' region

Full DDHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 28 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary spastic paraplegia

For Autosomal recessive spastic paraplegia type 28 (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy

Similar variants

DDHD1 p.Asp228Gly Uncertain significance ★ ⚠ same residue
DDHD1 p.Ala193Val Uncertain significance ★★ ⚠ same condition
DDHD1 p.Ala94Pro Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg204Trp Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg288His Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg554Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg570Gln Uncertain significance ★★ ⚠ same condition
DDHD1 p.Arg588Gln 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/ddhd1-p-asp228 (accessed [today's date]).

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