Is DDHD2 p.Lys435= (c.1305G>A) pathogenic?

DDHD2 p.Lys435= (c.1305G>A) is classified Likely benign in DDHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-26). Very rare (popmax 0.00204%, nfe); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Lys435= (c.1305G>A)?

DDHD2 p.Lys435= (c.1305G>A) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Lys435= (c.1305G>A) in the general population?

DDHD2 p.Lys435= (c.1305G>A) is very rare (popmax 0.00204%, 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.Lys435=

c.1305G>A · rs372509717 · VCV1151936

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00204%, nfe)

Conditions

hereditary spastic paraplegia 54

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	donor loss · deltas
Pangolin	Δ0.42	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 0.55, phastCons 1
Overall
CADD	10.67	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00204% European (non-Finnish) · 24/1,178,790 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00149% 24/1,612,138 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.Lys435=
Coding: c.1305G>A
MANE Select: NM_015214
dbSNP: rs372509717
Type: single nucleotide variant
Location: chr8:38249764 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 435: 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.Lys435Asn Uncertain significance ★ ⚠ same residue
DDHD2 p.Lys435Arg 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

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-lys435 (accessed [today's date]).

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