Is DDHD2 p.Ile288= (c.864A>C) pathogenic?

DDHD2 p.Ile288= (c.864A>C) is classified Likely benign in DDHD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-11). Rare (popmax 0.264%, mid); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Ile288= (c.864A>C)?

DDHD2 p.Ile288= (c.864A>C) is associated with hereditary spastic paraplegia 54, hereditary spastic paraplegia (ClinVar).

How common is DDHD2 p.Ile288= (c.864A>C) in the general population?

DDHD2 p.Ile288= (c.864A>C) is rare (popmax 0.264%, mid) (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.Ile288=

c.864A>C · rs148904419 · VCV473076

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.264%, mid)

Conditions

hereditary spastic paraplegia 54

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 3.6	GERP -3.1, phastCons 1
Overall
CADD	9.351	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.264% Middle Eastern · 16/6,062 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.045% 727/1,614,114 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.264%	379
Ashkenazi Jewishnot grpmax-eligible	0.0709%	1,410
European (non-Finnish)	0.0514%	1,944
Remaining individualsnot grpmax-eligible	0.0496%	2,016
South Asian	0.0384%	2,602
African / African-American	0.012%	8,341
Admixed American	0.0117%	8,575
Finnishnot grpmax-eligible	0.00156%	63,956

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.Ile288=
Coding: c.864A>C
MANE Select: NM_015214
dbSNP: rs148904419
Type: single nucleotide variant
Location: chr8:38245757 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 288: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity)

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

Also linked: hereditary spastic paraplegia

For Autosomal recessive spastic paraplegia type 54 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

DDHD2 c.1126-2A>G Likely pathogenic ★★ same condition
DDHD2 c.1248+2T>C Likely pathogenic ★★ same condition
DDHD2 p.Arg232Ter Pathogenic ★★ same condition
DDHD2 p.Arg329Ter Pathogenic ★★ same condition
DDHD2 p.Arg516Ter Pathogenic ★★ same condition
DDHD2 p.Asp660His Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Gln286Ter Pathogenic/Likely pathogenic ★★ same condition
DDHD2 p.Trp115Ter 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/ddhd2-p-ile288 (accessed [today's date]).

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