Is DDHD2 p.Leu390= (c.1168C>T) pathogenic?

DDHD2 p.Leu390= (c.1168C>T) is classified Benign/Likely benign in DDHD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). Low-frequency (popmax 1.03%, afr); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Leu390= (c.1168C>T)?

DDHD2 p.Leu390= (c.1168C>T) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Leu390= (c.1168C>T) in the general population?

DDHD2 p.Leu390= (c.1168C>T) is low-frequency (popmax 1.03%, afr) (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.Leu390=

c.1168C>T · rs142190071 · VCV386289

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.03%, afr)

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 -0.15	GERP -3.2
Overall
CADD	0.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.03% African / African-American · 752/73,226 alleles

Filtering AF 0.966% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.942%

Overall 0.0518% 815/1,574,170 alleles · low-frequency exomes 373/1,421,878 · genomes 442/152,292 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.03%	97
Remaining individualsnot grpmax-eligible	0.0557%	1,795
Admixed American	0.0385%	2,597
South Asian	0.00349%	28,657
European (non-Finnish)	0.000433%	231,205

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.Leu390=
Coding: c.1168C>T
MANE Select: NM_015214
dbSNP: rs142190071
Type: single nucleotide variant
Location: chr8:38247755 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 390: a UniProt-annotated variant site (in spg54; likely pathogenic; loss of triacylglycerol hydrolase activity); the sam 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.Leu390Ile Uncertain significance ★ ⚠ same residue
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

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-leu390 (accessed [today's date]).

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