Is DDHD2 p.Leu93= (c.277T>C) pathogenic?

DDHD2 p.Leu93= (c.277T>C) is classified Conflicting classifications of pathogenicity in DDHD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-07-02). Ultra-rare (popmax 0.0271%, nfe); Associated with hereditary spastic paraplegia 54.

What condition is associated with DDHD2 p.Leu93= (c.277T>C)?

DDHD2 p.Leu93= (c.277T>C) is associated with hereditary spastic paraplegia 54 (ClinVar).

How common is DDHD2 p.Leu93= (c.277T>C) in the general population?

DDHD2 p.Leu93= (c.277T>C) is ultra-rare (popmax 0.0271%, 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.Leu93=

c.277T>C · rs544728429 · VCV434904

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0271%, nfe)

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 -2.8	GERP -4.5
Overall
CADD	5.315	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0271% European (non-Finnish) · 320/1,179,604 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0237%

Overall 0.0215% 346/1,611,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0271%	3,686
Remaining individualsnot grpmax-eligible	0.0144%	6,928
South Asian	0.0144%	6,961
African / African-American	0.00401%	24,917
Finnishnot grpmax-eligible	0.00156%	63,990

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.Leu93=
Coding: c.277T>C
MANE Select: NM_015214
dbSNP: rs544728429
Type: single nucleotide variant
Location: chr8:38234450 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.70
Residue 93: the wwe 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.Leu93Phe 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-leu93 (accessed [today's date]).

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