Is DDHD2 p.Phe601fs (c.1803del) pathogenic?

DDHD2 p.Phe601fs (c.1803del) is classified Pathogenic in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-26). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Phe601fs (c.1803del)?

DDHD2 p.Phe601fs (c.1803del) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Phe601fs (c.1803del) in the general population?

DDHD2 p.Phe601fs (c.1803del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Autosomal recessive spastic paraplegia type 54 inherited?

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

DDHD2 p.Phe601fs

c.1803del · rs1312739762 · VCV540287

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary spastic paraplegia 54

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 15 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,026 alleles

Overall 6.84e-05% 1/1,461,890 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: DDHD2
Protein: p.Phe601fs
Coding: c.1803del
MANE Select: NM_015214
dbSNP: rs1312739762
Type: Deletion
Location: chr8:38253036 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 601: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the ddhd domain

Full DDHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary spastic paraplegia 54 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive spastic paraplegia type 54 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

DDHD2 p.Lys124fs Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Glu414fs Pathogenic ★ same condition
DDHD2 p.Gly344fs Likely pathogenic ★ same condition
DDHD2 p.Ile405_Phe406insTer Likely pathogenic ★ same condition
DDHD2 p.Lys152fs Pathogenic ★ same condition
DDHD2 p.Tyr661fs Likely pathogenic ★ same condition
DDHD2 c.221-1_224del Uncertain significance ★ same condition
DDHD2 p.Ala454_Pro455del 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/ddhd2-p-phe601fs (accessed [today's date]).

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